PMID- 33725485
OWN - NLM
STAT- MEDLINE
DCOM- 20210614
LR  - 20210614
IS  - 1097-4164 (Electronic)
IS  - 1097-2765 (Print)
IS  - 1097-2765 (Linking)
VI  - 81
IP  - 9
DP  - 2021 May 6
TI  - Balancing cohesin eviction and retention prevents aberrant chromosomal interactions, 
      Polycomb-mediated repression, and X-inactivation.
PG  - 1970-1987.e9
LID - S1097-2765(21)00141-6 [pii]
LID - 10.1016/j.molcel.2021.02.031 [doi]
AB  - 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.
CI  - Copyright © 2021 Elsevier Inc. All rights reserved.
FAU - Kriz, Andrea J
AU  - Kriz AJ
AD  - Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, 
      USA; Department of Genetics, Harvard Medical School, Boston, MA 02114, USA.
FAU - Colognori, David
AU  - Colognori D
AD  - Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, 
      USA; Department of Genetics, Harvard Medical School, Boston, MA 02114, USA.
FAU - Sunwoo, Hongjae
AU  - Sunwoo H
AD  - Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, 
      USA; Department of Genetics, Harvard Medical School, Boston, MA 02114, USA.
FAU - Nabet, Behnam
AU  - Nabet B
AD  - Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical 
      School, Boston, MA 02115, USA; Department of Cancer Biology, Dana-Farber Cancer 
      Institute, Boston, MA 02115, USA.
FAU - Lee, Jeannie T
AU  - Lee JT
AD  - Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, 
      USA; Department of Genetics, Harvard Medical School, Boston, MA 02114, USA. 
      Electronic address: lee@molbio.mgh.harvard.edu.
LA  - eng
GR  - R01 GM058839/GM/NIGMS NIH HHS/United States
GR  - R01 GM090278/GM/NIGMS NIH HHS/United States
GR  - R01 HD097665/HD/NICHD NIH HHS/United States
GR  - F31 HD100109/HD/NICHD NIH HHS/United States
GR  - HHMI/Howard Hughes Medical Institute/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20210315
TA  - Mol Cell
JT  - Molecular cell
JID - 9802571
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Chromosomal Proteins, Non-Histone)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Polycomb-Group Proteins)
RN  - 0 (Proteins)
RN  - 0 (RNA, Long Noncoding)
RN  - 0 (Rad21 protein, mouse)
RN  - 0 (WAPL protein, mouse)
RN  - 0 (XIST non-coding RNA)
RN  - 0 (cohesins)
SB  - IM
MH  - Animals
MH  - Cell Cycle Proteins/genetics/*metabolism
MH  - Cell Line
MH  - Chromosomal Proteins, Non-Histone/genetics/*metabolism
MH  - DNA-Binding Proteins/genetics/metabolism
MH  - Embryonic Stem Cells/*metabolism
MH  - Female
MH  - *Gene Silencing
MH  - Mice
MH  - Nucleic Acid Conformation
MH  - Polycomb-Group Proteins/genetics/*metabolism
MH  - Protein Conformation
MH  - Proteins/genetics/metabolism
MH  - RNA, Long Noncoding/genetics/*metabolism
MH  - Structure-Activity Relationship
MH  - *X Chromosome
MH  - *X Chromosome Inactivation
PMC - PMC8106664
MID - NIHMS1678113
OTO - NOTNLM
OT  - *Polycomb complexes
OT  - *WAPL
OT  - *X chromosome inactivation
OT  - *Xist RNA
OT  - *chromatin loops
OT  - *chromosome conformation
OT  - *cohesin
OT  - *compartments
OT  - *nuclear organization
OT  - *superstructures
COIS- Declaration of interests J.T.L. is a cofounder of Translate Bio and Fulcrum 
      Therapeutics and is an advisor to Skyhawk Therapeutics. B.N. is an inventor on 
      patent applications related to the dTAG system (WO/2017/024318, WO/2017/024319, 
      WO/2018/148440, and WO/2018/148443).
EDAT- 2021/03/17 06:00
MHDA- 2021/06/16 06:00
PMCR- 2022/05/06
CRDT- 2021/03/16 20:08
PHST- 2020/02/01 00:00 [received]
PHST- 2020/12/18 00:00 [revised]
PHST- 2021/02/22 00:00 [accepted]
PHST- 2022/05/06 00:00 [pmc-release]
PHST- 2021/03/17 06:00 [pubmed]
PHST- 2021/06/16 06:00 [medline]
PHST- 2021/03/16 20:08 [entrez]
AID - S1097-2765(21)00141-6 [pii]
AID - 10.1016/j.molcel.2021.02.031 [doi]
PST - ppublish
SO  - Mol Cell. 2021 May 6;81(9):1970-1987.e9. doi: 10.1016/j.molcel.2021.02.031. Epub 
      2021 Mar 15.