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*Current and/or Former Students*
The quickest way to get in touch with us if you are a current or former student is to call or text us at 503-575-9982. You can also easily send us an email (firstname.lastname@example.com)
*New to the Studio?*
If you are new to the studio (have not taken any classes or visited with us) please
use the NEW STUDENT form below. By filling out the NEW STUDENT form you can get your questions answered and/or schedule time to talk on the phone or meet at the studio with either of Sellwood Yoga's owners, sister and brother team: Savonn and Bill Wyland or our studio manager Claire. We will help you find classes that fit your needs and goals. Fill out the information below and one of us will get back to you within 24 hours.
PLEASE NOTE: We have two locations in Sellwood. Almost all of our Yoga and Pilates classes are held at Sellwood Yoga while our Barre, Bootcamp, FIT and some of our MELT Method classes are held at Align. Please double check the schedule to make sure you go to the correct location.
Sellwood Yoga: 7970 SE 13th Ave. (between SE Miller and SE Nehalem Streets)
Align Fitness: 8063 SE 17th Ave. (between SE Spokane and SE Tacoma Streets)
Please try arrive at least 15 minutes before class. Reserved spots that do not show may be given to standby students 5 minutes prior to class start time. Reservations may be cancelled online up to 30 minutes prior to class.
Sellwood Yoga: 7970 SE 13th Ave. (between SE Miller and SE Nehalem Streets)
Sellwood Yoga is located in Inner Southeast Portland in the historic Sellwood neighborhood. Our address is 7970B SE 13th Avenue between SE Miller Street and SE Nehalem Street, just a couple of blocks North of Tacoma St. The entrance to the studio is on the side of the building. Parking is usually easy to find along 13th Ave. or on the side streets. Places to secure your bike are also available along 13th. Sellwood Yoga is across the street from Grand Central Bakery and Sellwood Cycle Repair. We are close to Jade Teahouse, the Ugly Mug Coffeehouse, and the Blue Kangaroo Coffee Shop. New Seasons Market is not too far away from the studio.
Align Fitness: 8063 SE 17th Ave. (between SE Spokane and SE Tacoma Streets)
Align Fitness is located about 6 blocks away from the Sellwood Yoga studio. Align Fitness's address is 8063 SE 17th Ave between SE Spokane St. and SE Tacoma St. The entrance to the studio is on 17th Ave. Places to secure your bike are both in front of the studio as well as around the corner on SE Miller.
Align Fitness is next door to Bertie Lou's restaurant and near to Miller Paint Store.


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Andy Miller
Jump to
Long time character actor Andy Milder didn't develop an interest in acting until after attending the University of California at Berkeley. Milder majored in economics at Berkeley, and would later attend the American Conservatory Theater in San Francisco to pursue a career in entertainment. Milder began guest starring in television series during the early 1990s, with appearances on series like the coming of age classic "The Wonder Years," the family comedy "Empty Nest," and the crass sitcom"Married with Children," before landing a more significant role in the drama film "Apollo 13." Milder's breakthrough came in 1997 with a starring part in the short-lived yet critically acclaimed drama "Fame L.A.." Although Milder's role was recognized by critics, he was not able to parlay his recognition into more starring roles in the early 2000s, when he continued to appear in smaller guest roles in films and television series along with lending his voice to a couple of "Star Trek" video games. Milder would enjoy commercial and critical success in 2005, however, in the role of attorney Dean Hodes on Showtime's hit series "Weeds." Milder would land larger roles in films after the success of "Weeds" with appearances in the policital drama "Frost/Nixon" and the action blockbuster "Transformers" as well as a regular voice role in the animated action series "Legion of Super Heroes" and "Batman: The Brave and the Bold."

subset: commoncrawl


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Benazir's son to take up party mantle
Dubai: Bilawal, the eldest son of slain former prime minister of Pakistan Benazir Bhutto is expected to be the new chief of her Pakistan Peoples Party (PPP), Gulf News has learnt.
According to close family friends and the PPP leaders, a council of senior party leaders will also be formed to supervise the affairs of the party until BIlawal, who is currently studying at Oxford, is fully capable of handling the party affairs.
Bilawal will also read out a message which her mother left to explain the future of the PPP in the event of her death. Bilawal completed his high school in Dubai.
Meanwhile, secretary general of Pakistan Peoples Party Parliamentarians, told Gulf News from Larkana, home town of Benazir that they heard about Bilawal to be new party chief.
"The announcement about the future party leadership will be made after the Central Executive Committee meeting in Larkana on Sunday," he added.
Sources also disclosed that Zulfiqar Junior, son of the late Murtaza Bhutto, will also have some important role in the PPP.


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Well folks, I've completed all the worlds of Kingdom Hearts. I finished Neverland a few days ago and just finished Halloween Town yesterday. I wanna battle Oogie Boogie again though. He was actually a pretty fun boss. (The first part at least..not the second half) So now I'm on my way to the Hollow Bastion. How scary!! I've only been playing the game for 30 hours..and I'm almost done with it!:( Oh well, that means I'll be amped and ready for Kingdom Hearts 2 once I beat this one.
It looks like you're new here. If you want to get involved, click one of these buttons!


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The item may be missing its original packaging, or the original packaging has been opened or is no longer sealed. The item may be a factory second, or a new and unused item with minor defects.
Thank you for visiting The Zutons - You Can Do Anything on bananacorner.co.uk
We bring the products from many websites to one website for you to search, save and compare.


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Tierra LiCausi Shows Up At Women Tell All Taping For The Bachelor; Blames The Other Women For Her Behavior On The Show!
As always with attention-desperate reality stars, it was much ado about nothing!
After Tierra Li
CrazyCausi was threatening to make our day by NOT showing up at the The Bachelor's Women Tell All taping, sources say that not only did Tierra appear, but of course she fought with all the other girls!
While the rest of Sean Lowe's ladies held court on the stage ragging on how annoying she was, Tierra remained sequestered backstage until she was dragged into the hot seat by Chris Harrison.
"Everyone else was getting along great with each other," a source shares with WetPaint. "But they were ALL sh*t-talking Tierra."
Tierra LiCausi has really gotten the loser edit on this season's Bachelor. And it is one we all know she definitely deserved. Even Sean Lowe embarrassingly admits he was completely duped and said she had no business being on the show in the first place!
Tierra has apparently moved on and recently announced her engagement. She's also possibly completely done with Bachelor Nation (until Bachelor Pad waves a potential $250,000 in her face!). The Women Tell All special is taping today and one person is still undecided if she'll appear or not – Tierra!
"She's very upset with the way she came across on the show," an insider shares with Wetpaint. "At this point, all she wants is for everyone to forget about her. She knows going to Women Tell All will just draw more attention to how crazy she acted and how nasty she came across."
Sean Lowe visits the hometowns of his final four possible future wives – AshLee Frazier, Catherine Giudici, Lindsay Yenter, and Desiree Hartsock – this week on the Bachelor.
The hometown dates are usually either really boring, when the families are completely willing to accept the Bachelor into their lives after only two hours, or really awkward, when one or two family members remain skeptical and/or actively sabotage. Sean's hometown dates are no exception.
"Family is so big for me," Sean says. "This is a great week for me to really get a good sense of where these women come from." Based on the intro, it appears as if AshLee comes from Baggageville, Catherine's sisters are Cinderella levels of jealous, Lindsay comes from The Happy Locker, and Desiree's brother (Holla!) is a Menace II Reality TV Love.
Well these girls certainly don't pine for Sean Lowe for long do they! Imagine The Bachelor not being real love…
Shortly after being denied a rose and the chance for more and more elaborate vacations and publicity, errrr… I mean more time with Sean, the ladies are moving on!
And Selma Alameri knows how to pick'em! The super hot Selma is apparently now dating former Bachelorette runner-up Arie Luyendyk. Swoon!
"They're officially dating," an insider dishes to In Touch. "She went to Arizona and visited him already." However, a source
Emily Maynard claims Arie's motives are suspect! "He's hanging onto fame. Of course, he's dating someone from the show!"
Selma Alameri Dishes About Her Bachelor Experience; Sean Lowe Blogs About Cutting Lesley Murphy And Tierra LiCausi
Selma Alameri is/was one of my favorite bachelorettes on the Bachelor this season. Please. Don't confuse "favorite bachelorette" with "the one" for Sean Lowe. It is more about whom I find entertaining and likable and less about whom I think Sean should pretend to be in love with for three to six months. 😉
Unfortunately, Sean kicked Selma to the curb after she refused to take part in the Polar Bear Plunge in Canada. Personally, I wouldn't have done it either, and I admire Selma for staying true to herself rather than selling out for a one in nine chance at a
bound-to-fail relationship with Sean.
Sean tried to talk Selma into taking the plunge – saying things like you only live once and once in a lifetime opportunity – but she stood her ground. "I told him that if anybody was in danger, I would jump in and save them," Selma said. "But just to jump in for no reason, just to prove something to somebody, I said 'I don't feel like I should put my life at risk like that.' Once I have it in my head, 'no is no' – I won't be peer pressured."
Former Bachelorette Ali Fedotowsky Shares Major Behind The Scenes Dirt; Sex Was A "Vicious Cycle" For Bachelor Sean Lowe
Are you ready for some MAJOR dirt from one of the former Bachelorettes? I promise her name doesn't sound like Hey Nerd! Ali Fedotowsky was the franchise's sweetheart, first leaving Jake Pavelka during his season and then finding romance (and then heartbreak) with Roberto Martinez. Of course, we already know those deets…we want to hear about what goes on behind the scenes. Ali reveals that she did the hippity dippity on just one of her overnight dates, but she admits it could have happened with more than one guy if one of her favorites hadn't headed back to his girlfriend before her season's end. She also shares that one former Bachelor (try to guess who before clicking below!) used to take girls into the bathroom on group dates to test the merchandise! I think you'll also be shocked to hear who she thinks was the victim of a very bad edit. This is juicy stuff, y'all!
Oh yeah, and then there's Sean Lowe. I jest…it's just that Ali's chat has some great little nuggets! ABC has announced a new twist in the realm of Bachelor specials. Also, Sean dishes why he is choosing abstinence until marriage. I guess that's a little dirt from Sean. 🙂


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Guitar Compass features hundreds of free guitar lesson videos. These lessons are designed to teach you how to play guitar by covering the absolute basics up to more advanced soloing concepts and techniques. The lessons span different difficultly levels and genres like blues, rock, country, and jazz. Each lesson is designed to introduce you to a subject and get to know our instructors and their teaching style. To access more lessons and in-depth instruction, try a free 7 day trial of our premium membership.
Featured Lesson
Basic Strumming & Chord Changes is a free lesson for the beginner or intermediate player that wants to develop their strumming and chord changing abilities. Peter Vogl will provide step by step instruction on how to play some easy chords and basic but very useful strum patterns. We'll start by covering the Em and B7 chords and how to switch between them. We'll then practice along with the track using one down strum per measure. From there, we'll add two, then three, and four strums per measure. Keep practicing with the video until you are able to change chords and stay in time with the backing track. Click here to access the tabs and jam track.
Beginner Lessons
Acoustic Guitar
Blues Guitar Lessons
Electric Guitar
- Albert Lee Style Lick
- Basic Country Guitar Lick
- Learn to Play Country Bends
- Brent Mason Style Lick in E
- Cascading Lick
- Country Rock Guitar Solo
- D Country Lick
- Beginning Hybrid Picking Lick
- Country Thirds
- Intro to Cross Stringing Scales
- Chromatic Cross Stringing Scales
- Snapping and Popping
- Melodic Country Lick
- Vince Gill Guitar Lesson
- Jazz Guitar Comping Lesson
- Intro to 2-5-1 Chords
- 2-5-1 Line in C
- All The Things You Are – Intro
- C Major 7 Arpeggio
- Dominant Jazz Blues Chords
- Mike Stern Style Lick
- Minor 2-5-1 Chords
- Minor 2-5-1 with Moveable Chord Shapes
- John Scofield Style Lick
- Scott Henderson Style Lick
- Jazz Blues Solo in F
- Voice Leading Within the 2-5-1


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Catch Up on 50 Years of the X-Men With These 10 Key Stories
Want to catch up with the adventures of the X-Men now that they've hit their 50th birthday? Here's a quick guide to their greatest moments...
After $200 Million, Darpa Gives Up on Formation-Flying Satellites
Darpa is ending its experiment with small, close-flying spacecraft, but that doesn't mean the concept is dead.
Tomorrow, Celebrate Your Local Record Store by Buying These Special Releases
Tomorrow sees shops across the world take part in Record Store Day, offering exclusive releases from all kinds of artists. Here're some of our favorites.
Video: Darpa's Robots Practice Scavenging Space Junk From Satellites
Darpa's newest space program, detailed in this video, is downright ghoulish: Robots will soon harvest working antennas off dead satellites to make cheaper mini-sats.
Cereal-scape Photos Take Playing With Your Food to the Next Level
Most people are too groggy in the morning to pay attention to their cereal, but Ernie Button is not like most people. He specializes in...
Pentagon's Zombie Satellite Program Comes to Life
The Pentagon's intergalactic black-magic plot is getting ready to raise the dead. Dead satellites, that is.
Pentagon Plan: Watch a Satellite's Every Move — From 22,000 Miles Away
The Pentagon's mad-science division recently launched a mind-bending plan to harvest dead satellites for useful parts. But the orbital recycling mission won't work, unless the...
Sept. 7, 1948: Where the Rubber Is the Road
A mile-long stretch of Exchange Street in Akron, Ohio, is the first in the United States to be paved with a rubber-asphalt compound.
Wired Playlist: Hope Sandoval, King Khan, Air, The Heavy, Phoenix
This week's playlist features new music from artists we can't get enough of: Hope Sandoval and the Warm Inventions, The King Khan BBQ Show, Air,...
Computer Makers Aim to Banish Boot-Up Blues
In the time it takes your computer to boot up, you can probably make some toast or a cup of tea before the thing is...


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NanoMarkets Releases New White Paper on Printable Electronics Markets
Aug 23, 2005, 01:00 ET from NanoMarkets
GLEN ALLEN, Va., Aug. 23 /PRNewswire/ -- NanoMarkets, a leading industry consulting firm based here, today announced the release of a new white paper titled, "A Roadmap for Printable Electronics" that examines the market opportunities and product timeframes for printable electronics. The research on which this paper is based was drawn from NanoMarkets' new report, "Printable Electronics: Roadmaps, Markets and Opportunities," that will be released the week of August 29th. The paper can be accessed from the firm's website at http://www.nanomarkets.net or by emailing a request to email@example.com. Synopsis: Printable electronics promises to create circuits using organic polymer or nanometallic inks, laid down using either conventional printing technologies, such as offset, or with ink-jet printers, such as the systems currently being developed by Litrex and Dimatix. This new way of creating electronics will lead to a variety of new products that could not be created using conventional CMOS processes. These new products are likely to include printed RFID tags that will be inexpensive enough to compete with barcodes, highly flexible computer displays, and photovoltaic arrays that can be printed directly onto roofing and wall-building materials. These future products, and more, are now being routinely touted by materials equipment and electronics firms that are active in this space, such as 3M, Cambridge Display Technology, DuPont, Hitachi, Motorola, Philips and Plastic Logic. Analysis by NanoMarkets suggests that within two or three years printable electronics will become widely available. However, it is also clear from NanoMarkets' research that companies in the printable electronics market hold different views on the timetable for printable electronics. Estimates of commercial viability can differ by as much as four years. The new white paper illustrates a possible product roadmap for the printable electronics industry based on what the firm views to be possible technologically and from demand- side analysis. About NanoMarkets: NanoMarkets' mission is to measure the impact of new technologies on both established and emerging markets with a focus on the realms of electronics, energy and bio-medical markets. Through its reports, market briefs and customized client engagements NanoMarkets' clients are able to receive insightful value-chain analyses that determine where and how nanotechnology will impact both their business operations and profit potential. Visit http://www.nanomarkets.net for additional details about the company.
SOURCE NanoMarkets


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Welcome to the Edinburgh Airport Guide - the definitive resource to help you find everything you need when travelling to, from and around Edinburgh Airport.
- Book Cheap Edinburgh Flights
- Airport code: EDI
- +44 (0)870 040 0007
- 12km from Edinburgh
- Airport Postcode: EH12 9DN
Edinburgh Airport Guide has been developed to provide a handy reference for those travelling to, from or through Edinburgh Airport.
Edinburgh airport provides a wide range of facilities including those for business, children and disabled travellers. Public transportation to and from the airport is reliable and frequent with a choice of trains, coaches, taxis and car hire.
Edinburgh airport has one terminal which serves 30 different airlines flying to a number of destinations.
Those wishing to drive to the airport will find it easily accessible and well sign posted from the access roads. The airport offers a range of valet, short and long stay parking.
Staying at Edinburgh Airport? Book a hotel!
Whether you have an early flight or have to stay at the airport during the night, airport hotels are always the best option.
Find hotel deals at Edinburgh Airport in our hotels page, and start your holiday now!Order Foreign CurrencySave time by comparing and ordering your commission free foreign currency now!
Travel Extras
Book online with National Express coaches to and from Edinburgh Airport and travel across all the UK!
Save up to 78% on your long stay parking costs by comparing all airport parking providers and booking online!
Find out about what services Edinburgh Airport offers for those requiring special assistance.
Make the most of duty free by planning your airport shopping online.
Latest Edinburgh Airport News
Edinburgh Airport has plans to expand its facilities! They have launched a consultation period which will be open for 6 weeks, to allow the public to provide their feedback on the details of the pro...[ Read More ]
Edinburgh Airport have revealed that August was the 5th consecutive month where passenger numbers exceeded 1 million, a trend that began in April. August also marked a great year on year growth patter...[ Read More ]
Scotland's busiest airport is celebrating their 100th year of being open today. It was on this day in 1916 that Edinburgh Airport opened as a Royal Flying Corps aerodrome, named Turnhouse, which was...[ Read More ]
Both Edinburgh and Glasgow airports have seen a significant rise in passengers in the recent months. This is said to be due to more international routes being added from both of the airports. The figu...[ Read More ]
Edinburgh Airport is undergoing a great new expansion plan. The terminal building is on the move with plans for it to take the area that was the airport's coach park. The new terminal building will ...[ Read More ]


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Get Men's Fitness Daily Newsletters
Subscribe to Men's Fitness and get up to 80% OFF the newsstand price!
Get the custom digital edition for your iPad or iPhone now!
It's the equivalent to anger management.
Hopefully it's not from gnawing on barbells.
Optimize your gym time with these key maxims.
Fortunately, you have other options.
Because nothing ruins workout mojo like screaming joints.
Grab some major muscle gains by going "barefoot" (or close to it).
Make sure you get the benefits of this recovery method.
The truth behind these fitness misconceptions.


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I have a Caldera 3.0 I just bought brand new.
On Break-in (Tank 1 - Idle), the spring on the clutch shoes broke. Purchased replacment shoes/spring. Tank # 6, springs broke again.
Does anyone know of a Better Clutch Setup? I'm thinking about a 3 or 4 shoe setup.
Can anyone point me to one that is compatable?<br type="_moz" />


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Showing 1-24 of 45 items found in Food & Drink
- Sort by:
Taste the tradition of over 100 years of quality grown fruit from the Mazanek family orchards. Even connoisseurs will appreciate a glass of John James, a delightful semi-sweet blend of Golden Delicious and Jonathan apples aged in American oak.
Dine in or carry out of Bar-B-Que, ribs, chunk cod fish, steaks and chicken.
Offers full lunch and dinner menu along with homemade desserts. We specialize in hand-cut steaks.
Historic, elegant, fine dining featuring steaks, fresh seafood, exquisite entrees, cocktails and fine wine. Open for lunch, dinner and banquets for 100+.
Homecooking away from home. Daily lunch specials.
Chinese food served in a family atmosphere.
Enjoy fine handcrafted Illinois wines served with a personal touch in a relaxing country atmosphere. Experience the outdoor beauty of Southwestern Illinois' rolling farmland or sip wine indoors by a cozy fire.
Tequila Mexican Restaurant offers delicious Mexican food at a great price with fabulous, fast, and friendly service.
Winery, restaurant, and lakeside event pavilion. Lots of outdoor seating. Great place for a relaxing day away or to gather with friends.
This craft brewery will satisfy the thrist of beer drinkers looking for locally brewed IPA and other house specialties.
Hoffman House offers delicious food in a casual, elegant atmosphere.
Home of the Uncle Joe's All Purpose Sauces. Located at Exit 83 on Interstate 57 near Rend Lake.
Mexican Restaurant. See other locations.
CITY:Mount Vernon
Country cooking.
CITY:Mount Vernon
Our menu features everything you love about country cooking, plus a few items that might just surprise you.
CITY:Mount Vernon
Family restaurant with country cooking.
CITY:Mount Vernon
Barbeque is the specialty here.
CITY:Mount Vernon
Bar & grill.
CITY:Mount Vernon
Chili's Grill & Bar - Mt. Vernon
Mexican food.
CITY:Mount Vernon
Country Cooking Restaurant
CITY:Mount Vernon
Greek restaurant with homemade desserts, soups and dishes.
CITY:Mount Vernon
The Frosty Mug Bar & Grill is a great place to bring the whole family for lunch or dinner. Located in Mt Vernon, IL, the Frosty is a restaurant and bar with daily lunch specials at affordable prices. Stop in for a great meal served by a friendly staff and see what you've been missing!
CITY:Mount Vernon
Sandwiches, snacks and drinks. Located inside a bowling alley.
CITY:Mount Vernon
Home to outstanding food and drinks, a great atmosphere for sports and families.
CITY:Mount Vernon


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$50 no deposit bonus at Kings Chance Casino
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Recap - Milwaukee Defeats Houston 5-3
Houston dropped a 5-3 decision at Minute Maid Park on Sunday as Milwaukee legged out a win behind winning pitcher Yovani Gallardo.
Milwaukee won as a -182 favorite, while Over-Under bettors who played OVER the total of 7.5 were rewarded at the payout window.
Milwaukee got 7 2/3 innings from Yovani Gallardo, who gave up 3 earned runs on 9 hits, while striking out 8. He earned the victory, while the Brewers got 1 RBI from Rickie Weeks in the win.
Houston's starting pitcher Jordan Lyles worked 7 innings, giving up 8 hits and 2 earned runs while striking out 5 in the loss. They got 2 hits from Tyler Greene in a losing cause.
The battle of the bats favored Houston as they had 10 hits, while Milwaukee only had 9.
Kameron Loe pitched the final 1 inning for the save. He struck out 2 and allowed 1 hit in his outing.
Milwaukee looks to continue its winning ways next game with a battle against Colorado. Houston will aim to get back on the winning track at Chicago.


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Schedule complete automatic backups of your WordPress installation. Decide which content will be stored (Dropbox, S3…). This is the free version
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Sidebar widget to log into WordPress Account
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Automatically replicate any plugin setting network-wide: apply sitewide settings. Spread your settings or options on all your multisite blogs. Options


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I noticed in both "Spider Man 2" and "The Incredibles" there was the same superhero stunt. Both Peter Parker, and Bob Parr stop an elevated train (based on the Chicago El) from running off the ends of the tracks by going in front, and pushing against the ties.
This obviously comes from somewhere? What I wonder is where? Superman?Powered by Sidelines


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Harold Kress doesn't have any movies playing in theaters.
If you feel like heading out, check out other movies in theaters.
No Questions Asked
Valley of the Kings
Count Your Blessings
Imitation General
Rage in Heaven
The Miniver Story
Broadway Serenade
The Great Sinner
Andy Hardy Meets Debutante
All Harold Kress films
Movies.com, the ultimate source for everything movies, is your destination for new movie trailers, reviews, photos, times, tickets + more! Stay in the know with the latest movie news and cast interviews at Movies.com.
Copyright © 2017 FANDANGO MOVIES.


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Rates in SGD (taxes & fees included), shown as:
Nightly Average
S$144 Avg. price/night
Dalbeattie Guest House
13 Maxwell Park, Dalbeattie DG5 4LR, United Kingdom
Find Hotel Rates
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Dalbeattie Guest House Hotel Reviews
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Dalbeattie Guest House Hotel Details
Check-in: 16:00
Check-out: 10:30
Enjoy your visit to Dalbeattie with a stay at Dalbeattie Guest House. Free self parking is an added perk, and guests looking to stay active can check out the nearby hiking/biking trails and mountain biking.
13 Maxwell Park Dalbeattie DG5 4LR, United Kingdom


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NASA, University of Washington team up to track rain, snow in soggy Washington
The field experiment on Washington's Olympic Peninsula attempts to validate, on the ground, how well global satellites measure precipitation from space.
IIT Kharagpur inks MoU with George Washington University
IIT Kharagpur has signed an MoU with the Law School of George Washington University ...
The Latest: Trump at Washington National Cathedral
10:45 a.m. President Donald Trump is opening his first full day in office by attending a prayer service at the Washington National Cathedral.
Chinese minister appeals to Washington to avoid 'trade war'
Gao said a trade war ``should not become an option.'' He appealed to Washington to ``properly solve'' disputes through ``dialogue and cooperation.''
Trump throws Washington into state of anxious uncertainty
WASHINGTON (AP) — Two weeks into his presidency, Donald Trump has thrown Washington into a state of anxious uncertainty. Policy pronouncements sprout up from the White House in rapid succession.
Washington state sues Trump over immigration order
Washington state's attorney general says he is suing President Donald Trump over an executive order that suspended immigration from seven countries with majority-Muslim populations and sparked nationwide protests.
In one week, Trump shakes up Washington and the world
Trump's down-to-the-studs gut job began with a feisty inaugural address: a call to arms that tested old distinctions between left and right.
Protesters climb a construction crane in Washington
Seven protesters scaled a construction crane in Washington, DC, to stage what is believed to be an environmental protest.
Anti-Trump protesters set to flood Washington
Trump's inaugural speech on Friday set the tone for his presidency: proudly populist, fiercely nationalist and determined to break with the legacy of his Democratic predecessor.
Protesters plan to disrupt Donald Trump's inauguration in Washington
At one of those protest outside the National Press Club, the police had to use pepper spray to disperse people who had gathered against what it called "the Alt-Reich" outside "DeploraBall" inside the building.
Trump sweeps into Washington with a wave and a salute
WASHINGTON (AP) — Ready for his big moment, Donald Trump swept into Washington on a military jet Thursday and quickly set to building better ties to the Republican Congress as he kicked off three days of inaugural festivities.
Trump arrives in Washington with a wave and a salute
WASHINGTON (AP) — Ready for his big moment, Donald Trump traded in his beloved private plane for a military jet Thursday and swooped into Washington for three days of inaugural festivities.
Trump pays surprise visit to his Washington hotel
WASHINGTON (AP) — He just couldn't stay away. President-elect Donald Trump made a surprise visit to his Washington, D.C., hotel on Wednesday night, grabbing a late dinner while in town for a couple of fundraisers.
Thousands converge in Washington to attend Donald Trump's inauguration
The celebrations around Trump's inauguration beginning tomorrow has been organised around the theme 'Make America Great Again'.
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The report tracks the growing super-rich population in 125 cities across 89 countries and provides perspective on the issues that are influencing UHNWI investment and lifestyle decisions.


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Dissecting the expression landscape of RNA-binding proteins in human cancers
- Bobak Kechavarzi1 and
- Sarath Chandra Janga1, 2, 3Email author
DOI: 10.1186/gb-2014-15-1-r14
© Kechavarzi and Janga; licensee BioMed Central Ltd. 2014
Received: 1 August 2013
Accepted: 10 January 2014
Published: 10 January 2014
RNA-binding proteins (RBPs) play important roles in cellular homeostasis by controlling gene expression at the post-transcriptional level.
We explore the expression of more than 800 RBPs in sixteen healthy human tissues and their patterns of dysregulation in cancer genomes from The Cancer Genome Atlas project. We show that genes encoding RBPs are consistently and significantly highly expressed compared with other classes of genes, including those encoding regulatory components such as transcription factors, miRNAs and long non-coding RNAs. We also demonstrate that a set of RBPs, numbering approximately 30, are strongly upregulated (SUR) across at least two-thirds of the nine cancers profiled in this study. Analysis of the protein–protein interaction network properties for the SUR and non-SUR groups of RBPs suggests that path length distributions between SUR RBPs is significantly lower than those observed for non-SUR RBPs. We further find that the mean path lengths between SUR RBPs increases in proportion to their contribution to prognostic impact. We also note that RBPs exhibiting higher variability in the extent of dysregulation across breast cancer patients have a higher number of protein–protein interactions. We propose that fluctuating RBP levels might result in an increase in non-specific protein interactions, potentially leading to changes in the functional consequences of RBP binding. Finally, we show that the expression variation of a gene within a patient group is inversely correlated with prognostic impact.
Overall, our results provide a roadmap for understanding the impact of RBPs on cancer pathogenesis.
RNA-binding proteins (RBPs) have been identified as key regulatory components interacting with the RNA within a cell. Their function is largely dependent on their expression and localization within a cell. They may be involved in processes ranging from alternative splicing to RNA degradation. Combining together, RBPs form dynamic ribonucleoprotein (RNP) complexes, often in a highly combinatorial fashion that can affect all aspects of the life of RNA [1–3]. Due to their central role in controlling gene expression at the post-transcriptional level, alterations in expression or mutations in either RBPs or their binding sites in target transcripts have been reported to be the cause of several human diseases such as muscular atrophies, neurological disorders and cancer (reviewed in [4–7]). These studies suggest there is precise regulation of expression levels of RBPs in a cell. In fact, a recent system-wide study of the dynamic expression properties of yeast RBPs showed that RBPs with a high number of RNA targets are likely to be tightly regulated, since significant changes in their expression levels can bring about large-scale changes in the post-transcriptional regulatory networks controlled by them [8]. RBPs have also been shown to autoregulate their expression levels. Fluctuations in the expression of autoregulatory RBPs are significantly decreased [9]. These results show that a low degree of expression noise for RBPs is a characteristic feature of their normal state.
Cancer is a complex genetic disease and many of its regulatory factors have been identified as being irregularly expressed. In particular, changes in the normal expression of RBPs have been shown to alter their function leading to a cancer phenotype [10]. Enhanced eIF4E and HuR expression levels have been implicated in initiating translation of mRNAs encoding mostly for pro-oncogenic proteins and other cancer-promoting processes. For instance, Sam68 regulates the alternative splicing of cancer-related mRNAs [10]. Yet another example is the cell-specific alternative splicing of FAS (Fas cell surface death receptor, a member of the TNF receptor superfamily) mRNA. This has been linked to cancer predisposition depending on whether the pro- or anti-apoptotic protein form is produced as a result of the interplay between various RBPs on the FAS transcript [11–14]. In some cases, disruption of the functionality of RBPs, although without directly acting on oncogenic genes, has been shown to affect alternative splicing regulation or the regulation of alternative cleavage mechanisms on transcripts, which can lead to the development of cancer [15, 16].
In a recent study, Castello and co-workers [17] utilized cross-linking and immunoprecipitation (CLIP) and photoactivatable-ribonucleoside-enhanced CLIP (PAR-CLIP) to isolate and validate, via proteomics, a set of approximately 850 high-confidence RBPs in humans. These approaches can be used to catalogue and study RBPs and their post-transcriptional networks in healthy and diseased states. By knowing the low degree of expression variation that is tolerated by RBPs in a healthy state and identifying them in mammalian systems, we can begin to investigate their dysregulation profiles in various disease conditions.
Results and discussion
RNA-binding proteins show significantly higher expression than non-RNA-binding proteins and other regulatory factors for 16 human tissues
In eukaryotes, transcription and translation occur in different compartments. This gives a plethora of options for controlling RNA at the post-transcriptional level, including splicing, polyadenylation, transport, mRNA stability, localization and translational control [1, 2]. Although some early studies revealed the involvement of RBPs in the transport of mRNA from the nucleus to the translation site, increasing evidence now suggests that RBPs regulate almost all of these post-transcriptional steps [1–3, 20]. RBPs have a central role in controlling gene expression at the post-transcriptional level. Alterations in expression and mutations in either RBPs or their RNA targets (the transcripts that physically associate with the RBP) have been reported to be the cause of several human diseases, such as muscular atrophies, neurological disorders and cancer [4–6, 21].
The fact that RBPs exhibit a particularly high level of expression in some tissues suggests a need for extensive post-transcriptional control of gene expression in them. For example, the coordinated and cyclic processes of spermatogenesis in testes necessitate the essential temporal and spatial expression of pertinent genes [23]. In the human prostate, slight alterations to the androgen receptor functionality [24] or transcription factors [25] have been shown to lead to a cancerous state. These trends suggest that a significant fraction of the RBPome might play an important regulatory role in diverse human tissues, although in some gonadal and developed tissues, RBPs and TFs had similar levels of expression. Our results show that the high expression of RBPs is especially important in developmentally important tissues suggesting that any patterns of dysregulation could strongly effect these tissues [8].
RNA-binding proteins are dysregulated across cancers and a subset are strongly upregulated across a majority of cancers
Based on our understanding of the expression landscape of RBPs in healthy human tissues, we next asked whether RBPs are dysregulated across cancers (see Materials and methods). Since expression data for healthy tissue was available for eight tissues from the Human BodyMap project corresponding to a set of nine different cancers profiled in the Cancer Genome Atlas (TCGA), we calculated the log-ratio of expression levels of RBPs in the healthy to cancerous states in each of the nine cancers (Materials and methods). Positive values represent a shift towards upregulation, or, more generally, increased transcript abundance. Negative log-ratios represent a trend of downregulation or decreased abundance. The log-ratio expression profile matrix for the nine cancers was hierarchically clustered to show patterns of similar dysregulation (Additional file 3: Figure S2 and Additional file 2: Table S1 includes log-ratio expression of RBPs). We observed that cancers in similar tissues (lung adenocarcinoma and lung squamous carcinoma) are clustered together suggesting a similar degree of dysregulation of the RBP repertoire. Our analysis also revealed that similar cancers, such as adenocarcinomas were clustered together. These trends indicate that expression ratios are reliable for profiling cancers with unique morphologies in various body locations.
Strongly upregulated RNA-binding proteins identified from nine cancers in humans and their cancer relevant references
Associated gene name
Coiled-coil domain containing 124
Cleavage stimulation factor, 3′ pre-RNA, subunit 2, 64 kDa
DEAD (Asp-Glu-Ala-Asp) box polypeptide 3, X-linked
Dyskeratosis congenita 1, dyskerin
Eukaryotic translation initiation factor 1A, X-linked
Family with sequence similarity 120C
Filamin A, alpha
Fragile X mental retardation 1
Guanine nucleotide binding protein-like 3 (nucleolar)-like
G1 to S phase transition 2
Heterogeneous nuclear ribonucleoprotein H2 (H')
HIV-1 Tat specific factor 1
HECT, UBA and WWE domain containing 1, E3 ubiquitin protein ligase
LAS1-like (Saccharomyces cerevisiae)
Muscleblind-like splicing regulator 3
Methyl CpG binding protein 2 (Rett syndrome)
Mex-3 homolog C (Caenorhabditis elegans)
NFKB repressing factor
Non-POU domain containing, octamer-binding
PHD finger protein 6
RNA-binding motif protein 10
RNA-binding motif (RNP1, RRM) protein 3
RNA-binding motif protein, X-linked
RNA-binding motif protein, X-linked 2
Retinitis pigmentosa GTPase regulator
Ribosomal protein L10
Ribosomal protein S4, X-linked
Solute carrier family 25 (mitochondrial carrier; adenine nucleotide translocator), member 5
Ubiquitin-like modifier activating enzyme 1
UPF3 regulator of nonsense transcripts homolog B (yeast)
UTP14, U3 small nucleolar ribonucleoprotein, homolog A (yeast)
We then asked whether tumor-matched normal expression data for TCGA samples can further support the set of SUR RBPs identified here. Although 'normal' site tissue samples from TCGA cannot provide an adequate control, since these samples are collected from a cancerous tissue and it is entirely feasible that the expression levels would still be in a state of dysregulation at the neighboring sites, this analysis can still provide an additional level of support for SUR RBPs. Additionally it is not possible to control for morphological types of tumors, which, depending on their type, can affect more than just the site of the tumor growth. Nevertheless, we profiled the tumor-matched normal expression levels that are available for eight of the nine cancer types with varying number of samples for breast (106 patients), colon (20 patients), kidney (69 patients), liver (49 patients), two types of lung cancers (57 and 50 patients), prostate (45 patients) and thyroid (58 patients). As suspected, we found the fold changes in expression for all the genes across eight cancers to be minimal (median [IQR] 0.055 [-0.28-0.39]), suggesting that tumor-matched normal expression data may not reflect a true healthy control. However, when we compared the fold changes in expression levels for RBPs and non-RBPs in the tumor-matched samples across cancers, we found that RBPs exhibited significantly higher fold changes compared to non-RBPs (median [IQR] 0.104 [-0.07:0.29] for RBPs versus median [IQR] -0.034 [-0.39:0.25] for non-RBPs, P < 2.2 × 10-16, Wilcoxon test) clearly indicating that RBPs are still significantly upregulated in tumors.
Further analysis to test for the enrichment of RBPs in the top quartile of upregulated genes across cancers revealed that RBPs are strongly over-represented in this list (P = 1.62 × 10-93, hypergeometric test). We also found that all the SUR RBPs are significantly dysregulated (P < 0.001, t-test comparing tumor and matched normal samples) in at least four of the eight cancers profiled (Additional file 2: Table S1). When we raised the stringency to identify an RBP to be dysregulated in at least six or more cancer types, we still found 24 of the original 31 SUR RBPs to be detected at P < 0.001. Very few SUR RBPs from the cancer types Kidney renal cell carcinoma (KIRC) and Liver Hepatocellular Carcinoma (LIHC) were found to be significantly altered in the tumor-matched analysis. While most of the SUR RBPs were found to be upregulated in the tumor-matched analysis, we also found cases of downregulation (Additional file 2: Table S1). Nevertheless, SUR RBPs as a group were also found to be strongly over-represented in the top quartile of the upregulated set in the tumor-matched analysis (P = 2.16 × 10-8, hypergeometric test), further supporting the notion that SUR RBPs identified using an external healthy control across a broad range of cancers are a confident set of dysregulated RBPs.
Non-RBP log-ratios showing the expression changes were also calculated using the external healthy data to determine if the proportion of strongly upregulated genes (SURs) in RBPs is significantly enriched. We found that the proportions were significantly different (P < 0.05, hypergeometric test) with RBPs having a higher proportion of SURs than non-RBPs. Several of these SUR RBPs were annotated to function in important biological processes, such as regulation of gene expression, transcriptional regulation and transport of biomolecules, although very few studies have explored their role in the context of post-transcriptional control, suggesting that their functional roles are far more diverse than previously understood and appreciated.
Of these RBPs classified as SUR RBPs, we note several that have already been implicated in complex genetic disorders and cancer or in cellular regulation and proliferation (Additional file 4: Table S2). Identified RBPs, such as NONO, are involved in RNA biogenesis and DNA double-strand break repair, and have been found to be regulated by other factors, when dysregulated potentially promote carcinogenesis [41]. DDX3X, a member of the DEAD box RNA helicase family, has been shown to affect Wnt pathways, which leads to the developments of cancers [27]. DDX3X has also been demonstrated to promote growth and neoplastic transformation of breast epithelial cells [28]. Another SUR RBP, LAS1L was identified to interact with PELP1, which is implicated in pancreatic cancers [53]. HUWE1 is a member of the HECT family of E3 ubiquitin ligases, which has been identified as being overexpressed in breast, lung and colorectal cancers [54]. Indeed, increasing evidence now points to the role of novel ubiquitin-protein ligases in binding to RNA [55, 56]. For instance, ubiquitin-like fold has been recently shown to be independently enriched in novel unconventional RBPs identified in the yeast genome [57]. The RNA-binding protein RBM3 is associated with cisplatin sensitivity, the probability of a patient becoming resistant to cisplatin treatment and a positive prognosis in epithelial ovarian cancer [46]. RBM3 has seldom been found expressed in normal tissues, but it is more expressed in common cancers, particularly for the nuclear expression of Estrogen-Receptor (ER) positive tumors. These findings suggest the possible utility of the gene as a positive prognostic marker [47, 48].
PHF6 encodes a plant homeodomain (PHD) factor containing four nuclear localization signals and two imperfect PHD zinc-finger domains and it has been proposed that it has a role in controlling gene expression [58]. Inactivating mutations in PHF6 cause Börjeson-Forssman-Lehmann syndrome, a relatively uncommon type of X-linked familial syndromic mental retardation [58–60]. Recent studies show that mutations of this gene are implicated in the development of T-cell acute lymphoblastic leukemia and mutations have been detected in other forms of leukemia as well, suggesting a strong role in tumorigenesis [43, 61]. For other nucleolar proteins such as dyskerin (DKC1), which is responsible for the biogenesis of ribonucleoproteins and telomerase stability, the loss or gain of functions is associated with tumorigenesis [30–32]. Filamin A (FLNA) is an actin-binding protein, which interacts with a number of proteins including signaling molecules and membrane receptors, and its expression has been correlated with metastases in prostate and lung cancers [33, 34]. A recent study demonstrated the role of FLNA as a nucleolar protein that associates with the RNA polymerase I (Pol I) transcription machinery to suppress rRNA gene transcription [62]. Although further confirmation of how the global RNA-binding role of unconventional RBPs, like the E3 ubiquitin ligase HUWE1, contribute to cancer is needed, increasing evidence suggests that several enzymes and kinases bind to RNAs to control numerous cellular processes [57, 63]. Recent genome-wide screens for novel RBPs further support these observations, suggesting that unconventional RBPs are enriched for enzymatic functions [57, 64]. Functional enrichment analysis of SUR RBPs using the DAVID functional annotation system [65] revealed that RNA splicing, nucleotide binding and ribosome biogenesis were the common biological processes associated with these proteins, with a significant fraction of them associated with nucleolus and nuclear lumen cellular components (Additional file 4: Table S2).
Our observations combined with the existing corpus of literature in support of the roles for several of these SUR RBPs in cancerous states, suggest that their dysregulation could be the cause or result of the cancer phenotypes, especially given that even slight alterations in the expression levels of RBPs can bring about large-scale changes in the RBP–RNA interaction networks that they control [8]. It is important to note that although some of these SUR genes shown in Table 1 have been described in relation to cancer, there is little evidence in support of their contribution to either being RBPs or their post-transcriptional network as a contributing factor for the cancer phenotype. Our results in this study implicate them as a strongly upregulated set of RBPs across multiple cancers. Our analysis also corroborates that these significantly dysregulated RBPs are not an artifact of aberrations in calculations, or due to variability in patient expression data mainly because: (1) most of our patient sample sets are at least of the order of 100 for the cancers studied and (2) fold changes in expression levels between healthy and cancerous states for each patient were used to calculate the median fold change in expression of an RBP to account for extreme outliers. Our results also emphasize that these high expression levels may be indicative of a major dysfunction of these RBPs in addition to dysregulation. For example, the mutated form of PHF6, which is implicated in various forms of leukemia, has higher expression. Alternatively, the change in expression may be a result of an upstream alteration in the regulatory mechanisms, for example NONO; another example is that NKRF expression is regulated by miR-301a [40]. The high expression of some of these RBPs may be the result of their normal physiological levels being too low compared to a cancer context, as is the case for the proposed positive prognostic marker, RBM3. So a natural question to ask is whether RBPs have some prognostic impact for cancer, starting from the trends that have been observed in this expression analysis.
Strongly upregulated and non-strongly upregulated RNA-binding proteins exhibit significantly different within-group path lengths and variability in expression is related to the number of interactions
Since our analysis of the shortest path lengths between RBPs from SUR and non-SUR groups suggested that the particular protein interaction partners of RBPs might play an important role in mediating or cascading the effect of dysregulation, we rationalized that the protein complex size and a RBP's occurrence frequency in protein complexes would be related to their sensitivity to dysregulation. RBPs long have been known to form protein complexes, and if a key component within a complex is dysregulated or malformed, it would affect its overall functionality. If a SUR RBP was very prolific we would expect that many patterns of dysregulation would occur downstream as a result of the formation of a faulty complex. Furthermore, if these SUR RBPs participate in smaller complexes, it may be that their dysfunction will not be regulated or counteracted by other members within the complex. From the CORUM data [67] (see Materials and methods), five SUR RBPs were identified and 172 non-SUR RBPs were identified. We found that for the two classifications of RBPs (SUR vs non-SUR), there were no significant differences in distributions for either complex size or complex frequency nor was there any correlation with expression levels (Additional file 6: Figure S4 and Additional file 7: Figure S5). While the current coverage of the experimentally characterized human protein complexes is very limited, these results indicate that SUR and non-SUR RBPs do not have significant differences in terms of their protein complex membership.
We next asked whether the variability in expression levels of an RBP across cancer patients is different between SUR and non-SUR RBPs. To address this question, we choose breast cancer as our disease model due to the fact that it is the cancer with the most patient samples in TCGA and would naturally be the most robust dataset for identifying variation in the fold changes in expression levels of a RBP. We found that SUR and non-SUR RBPs did not exhibit significantly different expression variation (P = 0.1212, KS test), which was measured as the median absolute deviation (MAD) in the expression fold changes between healthy and cancerous tissue across all the patients (see Materials and methods). However, an analysis to test the relation between expression variation and the number of protein interactions of an RBP revealed that the higher the expression variation, the higher the number of protein interaction partners of the RBP (Figure 4B). Indeed, we noticed a significant difference in the number of interactions in the classified levels of variability for RBPs (P = 9.247 × 10-16, low vs medium; P < 2.226 × 10-16, low vs high; P = 6.6556 × 10-16, medium vs high, KS test). In contrast, TFs did not exhibit such significant differences in the number of interactions with the classified levels of variability (P = 0.8931, low vs medium; P = 0.0014, low vs high; P = 0.01, medium vs high, KS test). However, for non-RBPs a significant difference was found between medium and high as well as between high and low levels of variability (P = 0.7519, low vs medium; P < 2.2 × 10-16, low vs high; P < 2.2 × 10-16, medium vs high, KS test). The observation that the higher the variability in expression of a RBP the more interactions it has, suggests that fluctuating RBPs whose expression is not tightly controlled might have more promiscuous (non-specific) protein interactions (and protein complexes) thereby leading to RNA off-targets at post-transcriptional level. Our results also suggest that such dysregulation may be suppressed or is minimal due to the lower number of interactions for RBPs with less variability in expression. Our analysis here has focused on the RNA expression levels of RBPs though it is likely that there will be influences from diverse post-transcriptional regulatory phenomena like alternative splicing, translation control and post-translational modifications, which will affect the ultimate protein levels. Our observations do provide evidence that RBPs with high variability in expression have a higher number of protein interactions.
Survival contributions of RNA-binding proteins in breast cancer is related to network proximity to strongly upregulated RBPs and variability in expression across patients
In this study, we investigated the gene expression profiles of RBPs in healthy humans for 16 tissues and found that RBPs are consistently and significantly highly expressed compared to other classes of genes (non-RBPs) as well as in comparison to well-documented groups of regulatory factors like transcription factors, miRNAs and lncRNAs. This, in concordance with previous research, emphasizes their importance in post-transcriptional regulatory control across all the tissues. To understand the expression profile changes in a disease state for hundreds of RBPs in the human genome, we obtained analogous RNA-sequencing-based expression data for a total of 2,876 patient samples spanning nine cancers from TCGA and calculated a log-ratio for expression between cancer and healthy states. We showed that there is a unique signature of approximately 30 RBPs that had significantly increased expression levels across six out of nine (two-thirds) cancers profiled. These could be clearly labeled as a set of SUR RBPs delineating them from the rest of the RBPs based on the change in expression levels. This proportion of SUR RBPs in the RBP population is greater than the proportion of SUR non-RBPs suggesting for the first time that the expression levels of a significant fraction of the RBPs are affected in cancerous states. Analysis of the protein–protein interaction network properties for SUR and non-SUR group of RBPs, suggested that the shortest path length distributions between SUR RBPs is significantly lower than that observed for non-SUR RBPs. This observation together with survival analysis based on path lengths suggests that not all the SUR RBPs might be directly implicated in cancer but rather that a cause-and-effect relation might hold between some of the SUR RBPs. This observation was further supported by the fact that the higher the expression variation of a RBP in breast cancer patients, the higher the number of protein–protein interactions. This indicates that fluctuating RBPs whose expression is not tightly controlled (with differing fold changes in expression levels across patients) might be involved in more promiscuous (non-specific) protein interactions thereby leading to variable RNA off-targets at the post-transcriptional level.
To further determine the prognostic impact in breast cancer patients we ranked the SUR and non-SUR RBPs based on path length. The two RBP groups had different distributions. We found that as the mean path lengths between SUR RBPs increased their contribution to prognostic impact increased, suggesting that SUR RBPs with higher network distances with respect to other SUR RBPs, are more likely to contribute independently to survival as they might influence a larger fraction of the dysregulated network of SUR RBPs. In contrast, when a non-SUR RBP had a shorter path to a SUR RBP, there was a significant prognostic impact. This suggests that they are closer to the actual contributors of pathogenesis at the post-transcriptional level; however, the longer the path lengths, the weaker the prognosis. To gain further insight into the contribution of these subsets of RBPs in the development of and survival with cancer, we compared the overall significance of the Kaplan–Meier P values (-log[P]) for groups of RBPs classified by their level of dysregulation (SUR vs non-SUR). This analysis revealed no significant differences between groups of SUR and non-SUR RBPs in terms of their prognosis for survival. However, we found that, in general, the higher the expression variation across patients, the lower the prognostic impact of the protein. Our results suggest that RBPs from our signature set with lower variation in expression levels across patients might be good starting points for studying the effect of RBPs in cancer pathogenesis since SUR RBPs with large expression fold changes might be downstream or there might be indirect effects (Additional file 8: Figure S6). Additionally, common factors that are dysfunctional along the shortest paths in the protein interaction networks of SUR RBPs could also provide clues for potential drug targets as they can act as regulators for rewiring the post-translational landscape of RBPs thereby affecting RNP complex formation. With increasing efforts to uncover the binding sites of RBPs in higher eukaryotes using a variety of high-throughput approaches [69, 70], it should also become possible in the near future to study the differences in the target RNA pools between healthy and cancer genomes for several of these SUR RBPs. This would provide a global picture of the affected post-transcriptional regulatory networks. The global integration of networks governed by post-transcriptional players like miRNAs and RBPs together with signaling networks can provide a comprehensive picture of the cause of the dysregulation in these RBPs, which can be used to tease apart the contributions of local malfunctions and those due to an upstream or downstream effect in the cellular networks.
Materials and methods
Data for healthy expression of RNA-binding proteins in 16 human tissues
Our general workflow is illustrated in Figure 1. RNA-seq data for 16 different human tissues from ArrayExpress [71] (Accession no. E-MTAB-513), which is part of the Human BodyMap (HBM) 2.0 project [18, 22], was obtained for expression profiling. This data represents the healthy RNA transcript levels of male and female individuals aged 19 to 86, for 16 tissues: adipose, adrenal, brain, breast, colon, heart, kidney, liver, lung, lymph node, ovary, prostate, skeletal muscle, testes, thyroid and white blood cells. Expression data from the HBM project was quantified per transcript using the current annotations of the human genome from the Ensembl. This is available as reads per kilobase per millions of reads (RPKM) for each sample and hence can be compared across and within tissues. Therefore, each of the 16 tissues has a single RPKM value for the expression level of each transcript. A total of 850 genes experimentally characterized as RBPs in the human genome were obtained from a previous publication [17] and 4,647 transcripts associated with these RBPs were identified within the HBM set. The remaining set of 102,462 transcripts were classified as non-RBPs in this study. To examine the other regulatory factors in humans we obtained a set of 9,440 long non-coding RNAs (lncRNAs) from a Gencode study [18, 72], 529 microRNAs (miRNAs) from miRBase [73] and 1,231 transcription factors (TFs) from the DBD database [74] (Additional file 2: Table S1). For each of the 16 tissues we compared the distribution of the RPKM values for transcripts associated with RBPs and non-RBPs, as well as the distribution of expression levels of transcripts associated with RBPs with other regulatory factors to study their relative effect on regulatory control at the tissue level.
Data for cancer expression of RNA-binding proteins for nine cancers in humans
The cancer expression data was downloaded from TCGA [19]. TCGA provides multi-level data (clinical, genome sequencing, microarray, RNA sequencing and so on) procured from a number of institutions, from a variety of patients, for over 25 cancers. In this study, we collected RNAseq V2.0 data for 2,876 patients spanning nine cancers analogous to eight of our tissues in the HBM dataset: breast (850 patients), brain (175 patients), colon (193 patients), kidney (481 patients), liver (35 patients), two for lung (356 and 260 patients), prostate (141 patients), and thyroid (385 patients). TCGA accession numbers for the patient samples used in this study are available in Additional file 9: Table S3. For each cancer we collected the expression levels for each gene for all patients and determined a median representative level and MAD. This defines the genes' RNA expression levels and variability in the relevant cancer state. Likewise, cancer expression and variation were determined for the group of non-RBP genes from HBM as a complementary group for later network, interaction, and expression analyses. Hierarchical clustering of RBP expression for these nine cancers was performed in R, to determine if similar cancers and tissues group together (Additional file 3: Figure S2). Clustering results verified that the collected and amalgamated data are an accurate representation of their anatomical origin, and can be utilized to draw further conclusions.
Profiling for dysregulation of RNA-binding proteins and identification of strongly upregulated RNA-binding proteins across human cancers
For each gene identified as an RBP, we calculated a median expression level of its transcript products in the HBM data when there were multiple protein coding transcripts. To determine the extent of dysregulation in RBPs across cancers, we calculated for each cancer the log-ratio of the median expression in the cancer state over its expression in the associated healthy state. This allowed us to determine for the nine cancers if a particular gene annotated as an RBP is upregulated, downregulated or does not change in expression level in cancer states. Based on this analysis, if an RBP has a log-ratio of expression level greater than 9 across six or more of the studied cancers, we classified it as being SUR. Otherwise, it was categorized as non-SUR. We focused mainly on defining characteristics unique to these SUR RBPs that differentiate them from other RBPs and non-RBPs. SUR genes as defined here were also observed in non-RBPs and a hypergeometric test was performed to examine potential differences in the proportionality of SUR RBPs and non-SUR RBPs between the two functional classes. The genes associated with RBPs and non-RBPs were also classified by their level of expression variability in a cancer, measured as the MAD value of the fold change in expression for the profiled patients for the cancer. If a gene's variability within a cancer was above the 75th percentile, it was considered highly variable, below the 25th percentile it was considered least variable and the remainder were considered moderately variable.
Network and interaction properties of dysregulated RNA-binding proteins in human cancers
The most recent BioGRID [66] protein–protein interaction (PPI) information (version 3.2.97) was downloaded and used to construct an undirected network of interactions documented in humans. These interactions were used to determine if there were any differences in network properties between the two classifications of dysregulated RBPs, that is, SUR and non-SUR RBPs. This allowed the determination of the potential importance of the classifications for these RBPs. For example, if an SUR RBP forms a hub, it could cause patterns of dysregulation in other, associated interactors. We compared network centrality measures such as degree, closeness and betweenness as well as clustering coefficients and shortest paths between nodes, for different RBP classes utilizing the R package igraph [75]. For shortest paths, we calculated the mean shortest paths for a SUR RBP to other SUR RBPs and SUR RBPs to non-SUR RBPs. We also obtained the overall average path length between each RBP/non-RBP and SUR RBP/non-SUR RBP combination.
Manually curated experimentally characterized human protein complex data was obtained from CORUM [76], to determine the general promiscuity of RBPs in forming complexes. Then 5,217 protein complexes were mapped to the RBPs. We calculated for SUR RBPs and non-SUR RBPs the frequency of membership in CORUM complexes, as well as the mean complex size. This information together with the log-ratios of expression levels between healthy and cancer states in the tissues, allowed us to address whether SUR RBPs are enriched in protein complexes and/or occur in larger or smaller complexes. This analysis also allowed us to test the relation between the extent of an RBP's dysregulation in the context of its membership.
Determination of prognostic impact of RNA-binding proteins for breast cancer
A gene's prognostic impact is the gene's ability to impact positively or negatively patient survival. The prognostic impact for each gene was determined using data from the Kaplan–Meier (KM)-Plotter [68], which was determined from microarray experiments for over 20,000 genes for 1,800 breast cancer patients. For each gene in the RBP and non-RBP groups, we further categorized them as SUR or non-SUR and high or low variability in expression. We compared the significance [-log(KM-plotter P)] of the prognostic impacts within and between these groups.
Based on the network analyses, the genes were ranked in descending order based on their mean path lengths to the classification of dysregulated genes (SUR vs non-SUR). Path length calculations were determined from a distance matrix generated by the network analysis. From the ranked list of genes we selected five genes with the shortest and longest mean path lengths, and took a random sample of five genes with intermediate mean path lengths. This provided information on the prognostic impact associated with increased gene expression.
cross-linking and immunoprecipitation
Human BodyMap
- Kolmogorov–Smirnov test:
KS test
- lncRNA:
long non-coding RNA
median absolute deviation
- miRNA:
photoactivatable-ribonucleoside-enhanced CLIP
plant homeodomain
protein–protein interaction
RNA-binding protein
- RNA-seq:
RNA sequencing
reads per kilobase per millions of reads
strongly upregulated
the Cancer Genome Atlas
transcription factor
tumor necrosis factor
- KS test:
Kolmogorov–Smirnov test.
SCJ acknowledges support from the School of Informatics and Computing at Indiana University Purdue University Indianapolis (IUPUI) in the form of start-up funds. The authors would also like to thank members of the Janga Lab for providing helpful feedback in the course of this study and Sasan Hashemi for help with survival analysis using KM plotter.
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