Scientific Method / Science & Exploration

Derailing inflammation using a fake DNA packaging protein

A synthetic mimic of a protein that normally wraps up DNA can suppress the …

Researchers have figured out how to manipulate the packaging of DNA to shut down a harmful inflammatory response. Most of our cells contain the same complement of genes, but different cell types develop because they express genes at different times and levels. This continues to be true throughout our lives, as cells turn genes on or off in response to environmental signals. One way to switch genes on and off is to change the structure of the DNA. 

All DNA is spooled around proteins called histones. When it is wound more tightly, genes cannot be activated; when it is more relaxed, the DNA transcription machinery can get in. Histones that are chemically modified with an acetyl group bind to DNA loosely, and thus genes spooled around acetylated histones are more likely to be expressed.

Inflammation is used to mount an immune response, yet excessive inflammation can often damage their host. To modulate the expression of inflammatory genes, scientists have made a molecule that masquerades as an acetylated histone. 

The BET family of proteins assembles histone-containing complexes that regulate inflammatory gene expression. So the researchers called their fake histone I-BET, since it was found by screening synthetic compounds for those that can Interact with BET.

The researchers posited that I-BET may work in two ways. By binding to BET, it blocks the protein from binding to acetylated histones, thereby leaving them accessible to enzymes that can deacetylate them. But its binding to BET may also prevent the formation of large complexes on the DNA. 

I-BET has no obvious effect on its own. But, when it's around, immune cells have a reduced response to chemicals that are linked to bacterial infections. Those same chemicals can cause shock when injected into mice, but I-BET blocked that too.

I-BET seems to affect genes that come on later in the immune response; primary response genes were not affected. This is because these later genes had not yet formed the necessary complexes on their chromosomes to activate gene expression—their histones were not yet acetylated. This was the case in animals as well as cultured cells. 

This suppression of inflammation by I-BET is a proof of principle for drugs that that can selectively regulate gene expression by interfering with the assembly of histone dependent transcriptional complexes on the chromosomes. And it demonstrated that the epigenetic state of genes—the presence of acetylated histones at their promoters—is a phenomenon we can exploit to therapeutic ends.

Nature, 2010. DOI: 10.1038/nature09589  (About DOIs).

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9 Reader Comments

  1. New Asthma or allergy drug? Yes, please!
    Or new drugs for auto-immune diseases would be good. My mom suffers from fibromyalga and most of the treatment is for symptoms, not the root cause.
    694 posts | registered
  2. Carrie wrote:
    New Asthma or allergy drug? Yes, please!

    Yeah I think my mom suffers from fibromyalgia as well but she won't talk to her doctor about it. She's a horrible patient. Anyway my wife suffers from Crohn's/Colitis and this could be helpful for her as well.

    I have no idea how you would target the drugs to the right places if they were found to be helpful.
    1466 posts | registered
  3. Sounds like it's be good for rheumatoid arthritis too.
    65 posts | registered
  4. Such treatments certainly sound like they would be much safer and more reliable than corticosteriods, avoiding the nasty side effects.
    441 posts | registered
  5. This will be a wonder drug for those with inflamitory diseases.
    430 posts | registered
  6. Call me when there's a pill...
    9618 posts | registered
  7. If this can replace corticosteroids and the like, this has some sweet implications! Steroids can cause all sorts of problems, including cushing's syndrome which has it's own set of complications. Asthma and allergy patients such as myself need steroid-free treatment to avoid these complications.
    203 posts | registered
  8. This thread has honed in nicely on the big problem in all therapies: specificity. Whether we are discussing cancer, immune function, stem cells, gene therapy, or nuclear weapons, the challenge to target the desired time and place is more difficult than inventing the intervention.
    The work discussed here is a good starting place. It would be especially clever if a small molecule inhibitor (as discussed here) could be coupled to a big molecule that is"smart" in its delivery. But that is not the most popular kind of therapy. It can't be given as a pill, and costs a lot. So I repeat my call for more basic research that reveals fine details about these transcription complexes, and will permit subtle, rather than global, modulation.
    132 posts | registered
  9. Yeah... as someone in the midst of using steroid drops for uveitis/iritis... I really hope this develops into something that is an effective replacement for steroids. That would be awesome!
    114 posts | registered

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