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Regulation of single-cell genome organization into TADs and chromatin nanodomains

The genome folds into a hierarchy of three-dimensional (3D) structures within the nucleus. At the sub-megabase scale, chromosomes form topologically associating domains (TADs)1–4. However, how TADs fold in single cells remains elusive. Here, we revealed TAD features inaccessible to cell-population analysis by using super-resolution microscopy. TAD structures and physical insulation associated with their borders are variable between individual cells, yet chromatin intermingling is enriched within TADs compared to adjacent TADs in most cells. The spatial segregation of TADs is further exacerbated during cell differentiation. Favored interactions within TADs are regulated by cohesin and CTCF through distinct mechanisms: cohesin generates chromatin contacts and intermingling while CTCF prevents inter-TAD contacts. Furthermore, TADs are subdivided into discrete nanodomains, which persist in cells depleted of CTCF or cohesin, whereas disruption of nucleosome contacts alters their structural organization. Altogether, these results provide a physical basis for the folding of individual chromosomes at the nanoscale.

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We look forward to seeing the revised manuscript and thank you for the opportunity to review your work.
Sincerely, Tiago Tiago Faial, PhD Senior Editor Nature Genetics https://orcid.org/0000-0003-0864-1200 Reviewers' Comments: Reviewer #2: Remarks to the Author: The authors have provided a detailed response to the concerns raised about the interpretation of nonhomogenous chromatin staining patterns as a novel level of chromosome organization, which they define as chromatin nanodomains (CNDs). They acknowledge that similar patterns have been described before and argue that any functional role of these newly defined domains needs to await future studies. Given the lack of functional data and of knowledge of which genomic regions these CNDs would correspond to, I strongly recommend that the authors moderate their conclusions and point out the highly speculative nature of their definition of a new chromatin folding level before publication.
Reviewer #3: Remarks to the Author: The study by Szabo and colleagues reports two major new concepts. As discussed in the previous reviews, the measurements of TAD structure variability and the differential functional involvement of CTCF and the Cohesin complex are valuable insights. With the expanded interpretation provided in the newest rebuttal, I am now convinced that these concepts are of sufficient interest to the chromatin and nuclear organization communities that they warrant publication in Nature Genetics. Unfortunately, I still do not share the enthusiasm of the authors for the other major concept; the discovery of Chromatin Nanodomains (CNDs). Contrary to the author's argumentation (mostly in their response to Referee #2), I remain unconvinced that the insights into CND structure and function, which remain limited to a link with histone acetylation but not CTCF or Cohesin function, provide a similar level of insight as was presented when other chromatin domains/structures were presented. Unless additional characterization can be added (see my previous comments), the discovery of CNDs should not be the major focus of a publication in Nature Genetics.
To make the manuscript suitable for publication in Nature Genetics, I advise to shift the balance of the manuscript: expanding the sections on the variability of TAD structure and less emphasis on the identification of CNDs. Taking advantage of the increased length allowed by the Nature Genetics format, the authors could interpret the effect of CTCF and Cohesin removal in more detail (similar to the expanded interpretation in the rebuttal) and add additional comparison to previous studies based on single-cell Hi-C, population-based Hi-C with CTCF or Cohesin degrons and super-resolution microscopy (i.e. Bintu et al, 2018;Finn et al, 2019 and the recent publication by Luppino et al). The identification of CNDs could then be mentioned more in passing.

Author Rebuttal to Initial comments
According to the Reviewers comments, we have reshaped to manuscript in order to tone down the part related to CNDs and expand the single-cell organization of TADs in ESCs, differentiated NPCs, and on the differential roles of CTCF and cohesin in generating TADs. While the previous version contained 2 main Figures related to TADs and 2 others related to CNDs, the balance has been shifted in the revised version. This version now contains 3 main Figures related to TADs in ESCs (new Fig. 1), differentiated NPCs (new Fig. 2), CTCF-and RAD21-depleted cells (new Fig. 3), while the new Fig. 4 describes succinctly the internal organization of TADs into CNDs, accompanied with a model of 3D TAD folding which recapitulates all 4 Figures. Noteworthy, a new set of experiment in RAD21-depleted cells has been included in this revised version, which strengthens our conclusions regarding the different roles of CTCF and cohesin in the structural organization of TADs. These data are now presented in the new Fig. 3. The arrangement of the panels of the Extended Data were modified accordingly, and the text has also been adapted to fit this revised organization.

Reviewers' Comments:
Reviewer #2: Remarks to the Author: The authors have provided a detailed response to the concerns raised about the interpretation of non-homogenous chromatin staining patterns as a novel level of chromosome organization, which they define as chromatin nanodomains (CNDs). They acknowledge that similar patterns have been described before and argue that any functional role of these newly defined domains needs to await future studies. Given the lack of functional data and of knowledge of which genomic regions these CNDs would correspond to, I strongly recommend that the authors moderate their conclusions and point out the highly speculative nature of their definition of a new chromatin folding level before publication.
We have followed the recommendations of the Reviewer and have therefore substantially deemphasized the part related to CNDs, both in the text and in the Figures. The reorganization of the manuscript now allows a more detailed presentation of the folding of TADs in individual cells and the effects of CTCF and cohesin depletions in this organization, the latest being reinforced by new experiments in RAD21-depleted cells (presented in new. Fig. 3 and new Extended Data Fig. 5). Please see response to Reviewer #2 for further details.
Reviewer #3: Remarks to the Author: The study by Szabo and colleagues reports two major new concepts. As discussed in the previous reviews, the measurements of TAD structure variability and the differential functional involvement of CTCF and the Cohesin complex are valuable insights. With the expanded interpretation provided in the newest rebuttal, I am now convinced that these concepts are of sufficient interest to the chromatin and nuclear organization communities that they warrant publication in Nature Genetics.
We thank the Reviewer for supporting publication in Nature Genetics.
Unfortunately, I still do not share the enthusiasm of the authors for the other major concept; the discovery of Chromatin Nanodomains (CNDs). Contrary to the author's argumentation (mostly in their response to Referee #2), I remain unconvinced that the insights into CND structure and function, which remain limited to a link with histone acetylation but not CTCF or Cohesin function, provide a similar level of insight as was presented when other chromatin domains/structures were presented. Unless additional characterization can be added (see my previous comments), the discovery of CNDs should not be the major focus of a publication in Nature Genetics.
We understand the concern of the Reviewer regarding our current understanding of the mechanisms and function of the CNDs uncovered in this study. Following this recommendation, we have reshaped the manuscript so that this part is no longer a main focus of the study (see below).
To make the manuscript suitable for publication in Nature Genetics, I advise to shift the balance of the manuscript: expanding the sections on the variability of TAD structure and less emphasis on the identification of CNDs. Taking advantage of the increased length allowed by the Nature Genetics format, the authors could interpret the effect of CTCF and Cohesin removal in more detail (similar to the expanded interpretation in the rebuttal) and add additional comparison to previous studies based on single-cell Hi-C, population-based Hi-C with CTCF or Cohesin degrons and super-resolution microscopy Concerning the suggestion to present the effects of CTCF and cohesin removal in more details, we have added an entire set of experiments (shown in the new Figure 3) investigating the loss of TADs upon cohesin depletion. While in the previous version, only a limited set was analyzed (old Extended Data Fig.  8, in the new version a total of 15 chromatin regions were investigated in super-resolution microscopy, similarly to the set in CTCF-depleted cells. The results confirm and reinforce our conclusions presented in the last rebuttal regarding the two distinct mechanisms by which CTCF and cohesin shape TADs. Notably, even if the preferential intermingling of the chromatin within individual TADs is abolished upon both CTCF and cohesin depletion, different structural organizations are responsible for this loss of TADs. In CTCF-depleted cells, we observed ectopic interactions between adjacent TADs, consistent with a barrier function for CTCF separating different TADs (new Fig. 3a-e; new Extended Data Fig. 5a-c). On the other hand, in cohesin-depleted cells, we observed a severe reduction of intra-TAD contacts but no general ectopic inter-TAD intermingling (new Fig. 3a-c, f and g; new Extended Data Fig. 5d-f). Therefore, these results indicate a primary role for the cohesin complex in generating chromatin contacts, which result in intra-TAD intermingling while CTCF acts in preventing inter-TAD contacts, thus preventing chromatin intermingling between TADs.
Finally, the discussion was also reshaped and now further focuses on the comparison of our work with previous Hi-C, single-cell Hi-C and imaging studies, as well as on the roles of CTCF and cohesin.

Decision Letter, first revision:
21st Aug 2020 Dear Giacomo, Thank you for submitting your revised manuscript "Heterogeneous single-cell organization of chromosomes into TADs and chromatin nanodomains" (NG-LE54986R). It has now been seen by one of the original referees (#3) and their comments are below. The other reviewer (#2) declined to comment on the revised manuscript.
Reviewer #3 finds that the paper has improved in revision, and therefore we will be happy in principle to publish it in Nature Genetics, pending minor revisions to comply with our editorial and formatting guidelines. ** Note that I will send you a checklist detailing these editorial and formatting requirements in about a week. Please do not finalize your revisions or upload the final materials until you receive this additional information.** While we prepare these instructions, we encourage the Corresponding Author to begin to review and collect the following: --Confirmation from all authors that the manuscript correctly states their names, institutional affiliations, funding IDs, consortium membership and roles, author or collaborator status, and author contributions.
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Author Rebuttal, first revision: EDITORIAL REQUESTS:
AUTHOR RESPONSE: 1. Data presentation: Please ensure that data presented in a plot, chart or other visual representation format shows data distribution clearly (e.g. dot plots, box-and-whisker plots). When using bar charts, please overlay the corresponding data points (as dot plots) whenever possible and always for n ≤ 10. (Please see the following editorial for the rationale behind this request and an example https://www.nature.com/articles/s41551-017-0079).

Panels requiring revision:
Please note that data presentation has to be revised to comply with our policy in figure 4g.
We modified data presentation in figure 4g (and in extended data figures 7a, c, f in which similar bar plots are presented). 2. Statistics: Wherever statistics have been derived (e.g. error bars, box plots, statistical significance) the legend needs to provide and define the n number (i.e. the sample size used to derive statistics) as a precise value (not a range), using the wording "n=X biologically independent samples/animals/cells/independent experiments/n= X cells examined over Y independent experiments" etc. as applicable. Legends requiring revision: 1. Please note that this information is missing in the legends of figures 3e, g and extended data figures 3d, j; 4b, d, f; 8i.
2. Although 'n' is provided, please describe the nature of entity for 'n' in the extended data figures 3b, i.
We added this information in the legends.
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We strongly discourage deriving statistics from technical replicates, unless there is a clear scientific justification for why providing this information is important. Conflating technical and biological variability, e.g., by pooling technically replicates samples across independent experiments is strongly discouraged.
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All box plots need to be defined in the legends in terms of minima, maxima, centre, bounds of box and whiskers and percentile. Legends requiring revision: 1. Please note that the error bars need to be defined in the legends of figures 3e, g and extended data figures 4d, f; 8i.
2. Please note that the box plots need to be defined in terms of minima, maxima, centre, bounds of box and whiskers and percentile in the legends of figures 1c; 2g; 3c; 4f and extended data figures 3c, e, i, j; 4c, j; 6c; 7a, c, f; 8j.
We defined the error bars and the boxplots.

4.
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We detailed whether statistical tests were onesided or two-sided and noted exact p values, except in panels that display many p values, in which we kept stars for p values ranges (detailed in the legends) for readability.

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Please state in the legends how many times each experiment was repeated independently with similar results. This is needed for all experiments, but is particularly important wherever results from representative experiments (such as micrographs) are shown. If space in the legends is limiting, this information can be included in a section titled "Statistics and Reproducibility" in the methods section.
We added this information.
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We provided references for publicly available data and stated the availability upon request for others.

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We provided full scans in source data.

Micrographs:
Please ensure that all micrographs include a scale bar and this scale bar is defined on the panels or in the figure legends.
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The main test is now 2,600 words.
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