Chromatin alternates between A and B compartments at kilobase scale for subgenic organization

Hannah L. Harris, Huiya Gu, Moshe Olshansky, Ailun Wang, Irene Farabella, Yossi Eliaz, Achyuth Kalluchi, Akshay Krishna, Mozes Jacobs, Gesine Cauer, Melanie Pham, Suhas S.P. Rao, Olga Dudchenko, Arina Omer, Kiana Mohajeri, Sungjae Kim, Michael H. Nichols, Eric S. Davis, Dimos Gkountaroulis, Devika UdupaAviva Presser Aiden, Victor G. Corces, Douglas H. Phanstiel, William Stafford Noble, Guy Nir, Michele Di Pierro, Jeong Sun Seo, Michael E. Talkowski, Erez Lieberman Aiden, M. Jordan Rowley

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Nuclear compartments are prominent features of 3D chromatin organization, but sequencing depth limitations have impeded investigation at ultra fine-scale. CTCF loops are generally studied at a finer scale, but the impact of looping on proximal interactions remains enigmatic. Here, we critically examine nuclear compartments and CTCF loop-proximal interactions using a combination of in situ Hi-C at unparalleled depth, algorithm development, and biophysical modeling. Producing a large Hi-C map with 33 billion contacts in conjunction with an algorithm for performing principal component analysis on sparse, super massive matrices (POSSUMM), we resolve compartments to 500 bp. Our results demonstrate that essentially all active promoters and distal enhancers localize in the A compartment, even when flanking sequences do not. Furthermore, we find that the TSS and TTS of paused genes are often segregated into separate compartments. We then identify diffuse interactions that radiate from CTCF loop anchors, which correlate with strong enhancer-promoter interactions and proximal transcription. We also find that these diffuse interactions depend on CTCF’s RNA binding domains. In this work, we demonstrate features of fine-scale chromatin organization consistent with a revised model in which compartments are more precise than commonly thought while CTCF loops are more protracted.

Original languageEnglish
Article number3303
JournalNature Communications
Volume14
Issue number1
DOIs
StatePublished - 6 Jun 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2023, The Author(s).

Funding

Research reported in this publication was supported by the following: Cornelia de Lange Syndrome Foundation grant (S.S.P.R); National Institutes of Health grant T32-GM067553 (E.S.D); National Institutes of Health grant R35-GM128645 (D.H.P.); National Institutes of Health grant R35-GM139408 (V.G.C.); National Institutes of Health grant R35GM146852 (M.D.P.); National Institutes of Health grant R01-MH115957 (M.E.T.); CPRIT RR210018 (G.N.); National Institutes of Health grant U24 ~ HG009446 (W.S.N.); The Welch Foundation Q-1866 (E.L.A.); A McNair Medical Institute Scholar Award (E.L.A.); The NIH Encyclopedia of DNA Elements Mapping Center Award UM1HG009375 (E.L.A.); A US-Israel Binational Science Foundation Award 2019276 (E.L.A.); The Behavioral Plasticity Research Institute NSF DBI-2021795 (E.L.A.); NSF Physics Frontiers Center Award NSF PHY-2019745 (E.L.A., M.D.P., A.W.); National Institutes of Health grant RM1HG011016-01A1 (E.L.A., including support for I.F.); National Institutes of Health grants R00-GM127671 and R35-GM147467 (M.J.R.); The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

FundersFunder number
Behavioral Plasticity Research Institute NSFDBI-2021795
McNair Medical Institute
Welch Foundation Q-1866
National Science FoundationRM1HG011016-01A1, R35-GM147467, PHY-2019745, R00-GM127671
National Institutes of HealthR35-GM128645, UM1HG009375, R35-GM139408, R35GM146852, R01-MH115957, T32-GM067553, CPRIT RR210018, U24 ~ HG009446
Cornelia de Lange Syndrome Foundation
United States-Israel Binational Science Foundation2019276

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