Balancing Cohesin Eviction and Retention Prevents Aberrant Chromosomal Interactions, Polycomb-mediated Repression, and X-inactivation

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2021 Mar 16

PMID 33725485

Citations 19

Authors

Andrea J Kriz

David Colognori

Hongjae Sunwoo

Behnam Nabet

Jeannie T Lee

Affiliations

Soon will be listed here.

Abstract

Depletion of architectural factors globally alters chromatin structure but only modestly affects gene expression. We revisit the structure-function relationship using the inactive X chromosome (Xi) as a model. We investigate cohesin imbalances by forcing its depletion or retention using degron-tagged RAD21 (cohesin subunit) or WAPL (cohesin release factor). Cohesin loss disrupts the Xi superstructure, unveiling superloops between escapee genes with minimal effect on gene repression. By contrast, forced cohesin retention markedly affects Xi superstructure, compromises spreading of Xist RNA-Polycomb complexes, and attenuates Xi silencing. Effects are greatest at distal chromosomal ends, where looping contacts with the Xist locus are weakened. Surprisingly, cohesin loss creates an Xi superloop, and cohesin retention creates Xi megadomains on the active X chromosome. Across the genome, a proper cohesin balance protects against aberrant inter-chromosomal interactions and tempers Polycomb-mediated repression. We conclude that a balance of cohesin eviction and retention regulates X inactivation and inter-chromosomal interactions across the genome.

Citing Articles

Post-mitotic transcriptional activation and 3D regulatory interactions show locus- and differentiation-specific sensitivity to cohesin depletion.

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A biophysical basis for the spreading behavior and limited diffusion of Xist.

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Stepwise de novo establishment of inactive X chromosome architecture in early development.

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References

Fraser J, Williamson I, Bickmore W, Dostie J . An Overview of Genome Organization and How We Got There: from FISH to Hi-C. Microbiol Mol Biol Rev. 2015; 79(3):347-72. PMC: 4517094. DOI: 10.1128/MMBR.00006-15. View

Froberg J, Pinter S, Kriz A, Jegu T, Lee J . Megadomains and superloops form dynamically but are dispensable for X-chromosome inactivation and gene escape. Nat Commun. 2018; 9(1):5004. PMC: 6258728. DOI: 10.1038/s41467-018-07446-w. View

Lanctot C, Kaspar C, Cremer T . Positioning of the mouse Hox gene clusters in the nuclei of developing embryos and differentiating embryoid bodies. Exp Cell Res. 2007; 313(7):1449-59. DOI: 10.1016/j.yexcr.2007.01.027. View

Lee J . Gracefully ageing at 50, X-chromosome inactivation becomes a paradigm for RNA and chromatin control. Nat Rev Mol Cell Biol. 2011; 12(12):815-26. DOI: 10.1038/nrm3231. View

Flemr M, Buhler M . Single-Step Generation of Conditional Knockout Mouse Embryonic Stem Cells. Cell Rep. 2015; 12(4):709-16. DOI: 10.1016/j.celrep.2015.06.051. View

Hu B, Petela N, Kurze A, Chan K, Chapard C, Nasmyth K . Biological chromodynamics: a general method for measuring protein occupancy across the genome by calibrating ChIP-seq. Nucleic Acids Res. 2015; 43(20):e132. PMC: 4787748. DOI: 10.1093/nar/gkv670. View

Tarasov A, Vilella A, Cuppen E, Nijman I, Prins P . Sambamba: fast processing of NGS alignment formats. Bioinformatics. 2015; 31(12):2032-4. PMC: 4765878. DOI: 10.1093/bioinformatics/btv098. View

Wang J, MAGER J, Chen Y, Schneider E, CROSS J, Nagy A . Imprinted X inactivation maintained by a mouse Polycomb group gene. Nat Genet. 2001; 28(4):371-5. DOI: 10.1038/ng574. View

Vieux-Rochas M, Fabre P, Leleu M, Duboule D, Noordermeer D . Clustering of mammalian Hox genes with other H3K27me3 targets within an active nuclear domain. Proc Natl Acad Sci U S A. 2015; 112(15):4672-7. PMC: 4403207. DOI: 10.1073/pnas.1504783112. View

10.

Davidson I, Bauer B, Goetz D, Tang W, Wutz G, Peters J . DNA loop extrusion by human cohesin. Science. 2019; 366(6471):1338-1345. DOI: 10.1126/science.aaz3418. View

11.

Rao S, Huang S, St Hilaire B, Engreitz J, Perez E, Kieffer-Kwon K . Cohesin Loss Eliminates All Loop Domains. Cell. 2017; 171(2):305-320.e24. PMC: 5846482. DOI: 10.1016/j.cell.2017.09.026. View

12.

Wang C, Colognori D, Sunwoo H, Wang D, Lee J . PRC1 collaborates with SMCHD1 to fold the X-chromosome and spread Xist RNA between chromosome compartments. Nat Commun. 2019; 10(1):2950. PMC: 6610634. DOI: 10.1038/s41467-019-10755-3. View

13.

Weintraub A, Li C, Zamudio A, Sigova A, Hannett N, Day D . YY1 Is a Structural Regulator of Enhancer-Promoter Loops. Cell. 2017; 171(7):1573-1588.e28. PMC: 5785279. DOI: 10.1016/j.cell.2017.11.008. View

14.

Disteche C . Dosage compensation of the sex chromosomes and autosomes. Semin Cell Dev Biol. 2016; 56:9-18. PMC: 4955796. DOI: 10.1016/j.semcdb.2016.04.013. View

15.

Luppino J, Park D, Nguyen S, Lan Y, Xu Z, Yunker R . Cohesin promotes stochastic domain intermingling to ensure proper regulation of boundary-proximal genes. Nat Genet. 2020; 52(8):840-848. PMC: 7416539. DOI: 10.1038/s41588-020-0647-9. View

16.

Ramirez F, Ryan D, Gruning B, Bhardwaj V, Kilpert F, Richter A . deepTools2: a next generation web server for deep-sequencing data analysis. Nucleic Acids Res. 2016; 44(W1):W160-5. PMC: 4987876. DOI: 10.1093/nar/gkw257. View

17.

Darrow E, Huntley M, Dudchenko O, Stamenova E, Durand N, Sun Z . Deletion of DXZ4 on the human inactive X chromosome alters higher-order genome architecture. Proc Natl Acad Sci U S A. 2016; 113(31):E4504-12. PMC: 4978254. DOI: 10.1073/pnas.1609643113. View

18.

Merkenschlager M, Nora E . CTCF and Cohesin in Genome Folding and Transcriptional Gene Regulation. Annu Rev Genomics Hum Genet. 2016; 17:17-43. DOI: 10.1146/annurev-genom-083115-022339. View

19.

Rao S, Huntley M, Durand N, Stamenova E, Bochkov I, Robinson J . A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell. 2014; 159(7):1665-80. PMC: 5635824. DOI: 10.1016/j.cell.2014.11.021. View

20.

Huis In t Veld P, Herzog F, Ladurner R, Davidson I, Piric S, Kreidl E . Characterization of a DNA exit gate in the human cohesin ring. Science. 2014; 346(6212):968-72. DOI: 10.1126/science.1256904. View