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Fine-mapping of nuclear compartments using ultra-deep Hi-C shows that active promoter and enhancer elements localize in the active A compartment even when adjacent sequences do not

Huiya Gu, Hannah Harris, Moshe Olshansky, Yossi Eliaz, Akshay Krishna, Achyuth Kalluchi, Mozes Jacobs, Gesine Cauer, Melanie Pham, Suhas S.P. Rao, Olga Dudchenko, Arina Omer, Kiana Mohajeri, Sungjae Kim, Michael H Nichols, Eric S. Davis, Devika Udupa, Aviva Presser Aiden, Victor G. Corces, Douglas H. Phanstiel, William Stafford Noble, Jeong-Sun Seo, Michael E. Talkowski, Erez Lieberman Aiden, M. Jordan Rowley
doi: https://doi.org/10.1101/2021.10.03.462599
Huiya Gu
1Center for Genome Architecture, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Center for Theoretical Biological Physics, Rice University, Houston, TX, USA
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Hannah Harris
2Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA
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Moshe Olshansky
3Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
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Yossi Eliaz
1Center for Genome Architecture, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Center for Theoretical Biological Physics, Rice University, Houston, TX, USA
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Akshay Krishna
2Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA
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Achyuth Kalluchi
2Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA
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Mozes Jacobs
4Department of Genome Science, University of Washington, Seattle, USA; Paul G. Allen School of Computer science & Engineering, University of Washington, Seattle, USA
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Gesine Cauer
4Department of Genome Science, University of Washington, Seattle, USA; Paul G. Allen School of Computer science & Engineering, University of Washington, Seattle, USA
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Melanie Pham
1Center for Genome Architecture, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Center for Theoretical Biological Physics, Rice University, Houston, TX, USA
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Suhas S.P. Rao
1Center for Genome Architecture, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Center for Theoretical Biological Physics, Rice University, Houston, TX, USA
5Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
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Olga Dudchenko
1Center for Genome Architecture, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Center for Theoretical Biological Physics, Rice University, Houston, TX, USA
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Arina Omer
1Center for Genome Architecture, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Center for Theoretical Biological Physics, Rice University, Houston, TX, USA
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Kiana Mohajeri
6Massachusetts General Hospital, Boston, MA, USA
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Sungjae Kim
7Precision Medicine Institute, Seoul, 08511, Republic of Korea
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Michael H Nichols
8Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
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Eric S. Davis
9Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Devika Udupa
2Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA
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Aviva Presser Aiden
1Center for Genome Architecture, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Center for Theoretical Biological Physics, Rice University, Houston, TX, USA
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Victor G. Corces
8Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
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Douglas H. Phanstiel
9Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
10Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, NC, USA; Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC, USA
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William Stafford Noble
4Department of Genome Science, University of Washington, Seattle, USA; Paul G. Allen School of Computer science & Engineering, University of Washington, Seattle, USA
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Jeong-Sun Seo
7Precision Medicine Institute, Seoul, 08511, Republic of Korea
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Michael E. Talkowski
6Massachusetts General Hospital, Boston, MA, USA
11Department of Neurology, Harvard Medical School, Boston, MA, USA
12Program in Medical Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Erez Lieberman Aiden
1Center for Genome Architecture, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Center for Theoretical Biological Physics, Rice University, Houston, TX, USA
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  • For correspondence: erez@erez.com jordan.rowley@unmc.edu
M. Jordan Rowley
2Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA
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  • For correspondence: erez@erez.com jordan.rowley@unmc.edu
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Abstract

Megabase-scale intervals of active, gene-rich and inactive, gene-poor chromatin are known to segregate, forming the A and B compartments. Fine mapping of the contents of these A and B compartments has been hitherto impossible, owing to the extraordinary sequencing depths required to distinguish between the long-range contact patterns of individual loci, and to the computational complexity of the associated calculations. Here, we generate the largest published in situ Hi-C map to date, spanning 33 billion contacts. We also develop a computational method, dubbed PCA of Sparse, SUper Massive Matrices (POSSUMM), that is capable of efficiently calculating eigenvectors for sparse matrices with millions of rows and columns. Applying POSSUMM to our Hi-C dataset makes it possible to assign loci to the A and B compartment at 500 bp resolution. We find that loci frequently alternate between compartments as one moves along the contour of the genome, such that the median compartment interval is only 12.5 kb long. Contrary to the findings in coarse-resolution compartment profiles, we find that individual genes are not uniformly positioned in either the A compartment or the B compartment. Instead, essentially all (95%) active gene promoters localize in the A compartment, but the likelihood of localizing in the A compartment declines along the body of active genes, such that the transcriptional termini of long genes (>60 kb) tend to localize in the B compartment. Similarly, nearly all active enhancers elements (95%) localize in the A compartment, even when the flanking sequences are comprised entirely of inactive chromatin and localize in the B compartment. These results are consistent with a model in which DNA-bound regulatory complexes give rise to phase separation at the scale of individual DNA elements.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Figure layouts were changed to improve flow; author list and acknowledgments were updated according to additional information from collaboration; minor text corrections to reference new figure layout.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Fine-mapping of nuclear compartments using ultra-deep Hi-C shows that active promoter and enhancer elements localize in the active A compartment even when adjacent sequences do not
Huiya Gu, Hannah Harris, Moshe Olshansky, Yossi Eliaz, Akshay Krishna, Achyuth Kalluchi, Mozes Jacobs, Gesine Cauer, Melanie Pham, Suhas S.P. Rao, Olga Dudchenko, Arina Omer, Kiana Mohajeri, Sungjae Kim, Michael H Nichols, Eric S. Davis, Devika Udupa, Aviva Presser Aiden, Victor G. Corces, Douglas H. Phanstiel, William Stafford Noble, Jeong-Sun Seo, Michael E. Talkowski, Erez Lieberman Aiden, M. Jordan Rowley
bioRxiv 2021.10.03.462599; doi: https://doi.org/10.1101/2021.10.03.462599
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Fine-mapping of nuclear compartments using ultra-deep Hi-C shows that active promoter and enhancer elements localize in the active A compartment even when adjacent sequences do not
Huiya Gu, Hannah Harris, Moshe Olshansky, Yossi Eliaz, Akshay Krishna, Achyuth Kalluchi, Mozes Jacobs, Gesine Cauer, Melanie Pham, Suhas S.P. Rao, Olga Dudchenko, Arina Omer, Kiana Mohajeri, Sungjae Kim, Michael H Nichols, Eric S. Davis, Devika Udupa, Aviva Presser Aiden, Victor G. Corces, Douglas H. Phanstiel, William Stafford Noble, Jeong-Sun Seo, Michael E. Talkowski, Erez Lieberman Aiden, M. Jordan Rowley
bioRxiv 2021.10.03.462599; doi: https://doi.org/10.1101/2021.10.03.462599

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