TY - JOUR
T1 - BAZ2A safeguards genome architecture of ground-state pluripotent stem cells
AU - Dalcher, Damian
AU - Tan, Jennifer Yihong
AU - Bersaglieri, Cristiana
AU - Peña-Hernández, Rodrigo
AU - Vollenweider, Eva
AU - Zeyen, Stefan
AU - Schmid, Marc W
AU - Bianchi, Valerio
AU - Butz, Stefan
AU - Roganowicz, Marcin
AU - Kuzyakiv, Rostyslav
AU - Baubec, Tuncay
AU - Marques, Ana Claudia
AU - Santoro, Raffaella
N1 - Funding Information:
This work was supported by the Swiss National Science Foundation (310003A‐152854 and 31003A_173056 to R.S.; PP00P3_150667 to A.C.M.; NCCR RNA & Disease to R.S and to A.C.M.; 157488 and 180345 to T.B.), ERC grant (ERC‐AdG‐787074‐NucleolusChromatin to RS), Forschungskredit of the University of Zurich (to D.D, E.V., and M.R.), UBS Promedica Stiftung, Julius Müller Stiftung, Olga Mayenfisch Stifung, Sassella Stiftung, and Stiftung für wissenschaftliche Forschung an der Universität Zürich (to R.S.). We thank Peter Hunziker, Catherine Aquino, and the Functional Genomic Center Zurich for the assistance in sequencing and proteomic analysis. We also thank Dominik Bär for technical assistance. We thank C. Ciaudo for having provided ESC lines.
Funding Information:
This work was supported by the Swiss National Science Foundation (310003A-152854 and 31003A_173056 to R.S.; PP00P3_150667 to A.C.M.; NCCR RNA & Disease to R.S and to A.C.M.; 157488 and 180345 to T.B.), ERC grant (ERC-AdG-787074-NucleolusChromatin to RS), Forschungskredit of the University of Zurich (to D.D, E.V., and M.R.), UBS Promedica Stiftung, Julius M?ller Stiftung, Olga Mayenfisch Stifung, Sassella Stiftung, and Stiftung f?r wissenschaftliche Forschung an der Universit?t Z?rich (to R.S.). We thank Peter Hunziker, Catherine Aquino, and the Functional Genomic Center Zurich for the assistance in sequencing and proteomic analysis. We also thank Dominik B?r for technical assistance. We thank C. Ciaudo for having provided ESC lines.
Publisher Copyright:
© 2020 The Authors. Published under the terms of the CC BY NC ND 4.0 license
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - Chromosomes have an intrinsic tendency to segregate into compartments, forming long-distance contacts between loci of similar chromatin states. How genome compartmentalization is regulated remains elusive. Here, comparison of mouse ground-state embryonic stem cells (ESCs) characterized by open and active chromatin, and advanced serum ESCs with a more closed and repressed genome, reveals distinct regulation of their genome organization due to differential dependency on BAZ2A/TIP5, a component of the chromatin remodeling complex NoRC. On ESC chromatin, BAZ2A interacts with SNF2H, DNA topoisomerase 2A (TOP2A) and cohesin. BAZ2A associates with chromatin sub-domains within the active A compartment, which intersect through long-range contacts. We found that ground-state chromatin selectively requires BAZ2A to limit the invasion of active domains into repressive compartments. BAZ2A depletion increases chromatin accessibility at B compartments. Furthermore, BAZ2A regulates H3K27me3 genome occupancy in a TOP2A-dependent manner. Finally, ground-state ESCs require BAZ2A for growth, differentiation, and correct expression of developmental genes. Our results uncover the propensity of open chromatin domains to invade repressive domains, which is counteracted by chromatin remodeling to establish genome partitioning and preserve cell identity.
AB - Chromosomes have an intrinsic tendency to segregate into compartments, forming long-distance contacts between loci of similar chromatin states. How genome compartmentalization is regulated remains elusive. Here, comparison of mouse ground-state embryonic stem cells (ESCs) characterized by open and active chromatin, and advanced serum ESCs with a more closed and repressed genome, reveals distinct regulation of their genome organization due to differential dependency on BAZ2A/TIP5, a component of the chromatin remodeling complex NoRC. On ESC chromatin, BAZ2A interacts with SNF2H, DNA topoisomerase 2A (TOP2A) and cohesin. BAZ2A associates with chromatin sub-domains within the active A compartment, which intersect through long-range contacts. We found that ground-state chromatin selectively requires BAZ2A to limit the invasion of active domains into repressive compartments. BAZ2A depletion increases chromatin accessibility at B compartments. Furthermore, BAZ2A regulates H3K27me3 genome occupancy in a TOP2A-dependent manner. Finally, ground-state ESCs require BAZ2A for growth, differentiation, and correct expression of developmental genes. Our results uncover the propensity of open chromatin domains to invade repressive domains, which is counteracted by chromatin remodeling to establish genome partitioning and preserve cell identity.
KW - BAZ2A
KW - genome organization
KW - ground-state embryonic stem cells
KW - H3K27me3
KW - Topoisomerase 2A
UR - http://www.scopus.com/inward/record.url?scp=85092441864&partnerID=8YFLogxK
U2 - 10.15252/embj.2020105606
DO - 10.15252/embj.2020105606
M3 - Article
C2 - 33433018
SN - 0261-4189
VL - 39
SP - 1
EP - 23
JO - EMBO Journal
JF - EMBO Journal
IS - 23
M1 - e105606
ER -