Cohesin controls X chromosome structure remodeling and X-reactivation during mouse iPSC-reprogramming

Generoso, Serena Francesca, 1988-; Neguembor, Maria Victoria; Hershberg, Elliot A.; Sadreyev, Ruslan Ilyasovich; Kurimoto, Kazuki; Yabuta, Yukihiro; Ricci, Raffaele; Audergon, Pauline; Bauer, Moritz, 1987-; Saitou, Mitinori; Hochedlinger, Konrad; Beliveau, Brian J.; Cosma, Maria Pia; Lee, Jeannie T.; Payer, Bernhard

Cohesin controls X chromosome structure remodeling and X-reactivation during mouse iPSC-reprogramming

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dc.contributor.author Generoso, Serena Francesca, 1988-
dc.contributor.author Neguembor, Maria Victoria
dc.contributor.author Hershberg, Elliot A.
dc.contributor.author Sadreyev, Ruslan Ilyasovich
dc.contributor.author Kurimoto, Kazuki
dc.contributor.author Yabuta, Yukihiro
dc.contributor.author Ricci, Raffaele
dc.contributor.author Audergon, Pauline
dc.contributor.author Bauer, Moritz, 1987-
dc.contributor.author Saitou, Mitinori
dc.contributor.author Hochedlinger, Konrad
dc.contributor.author Beliveau, Brian J.
dc.contributor.author Cosma, Maria Pia
dc.contributor.author Lee, Jeannie T.
dc.contributor.author Payer, Bernhard
dc.date.accessioned 2023-09-26T06:30:51Z
dc.date.available 2023-09-26T06:30:51Z
dc.date.issued 2023
dc.description.abstract Reactivation of the inactive X chromosome is a hallmark epigenetic event during reprogramming of mouse female somatic cells to induced pluripotent stem cells (iPSCs). This involves global structural remodeling from a condensed, heterochromatic into an open, euchromatic state, thereby changing a transcriptionally inactive into an active chromosome. Despite recent advances, very little is currently known about the molecular players mediating this process and how this relates to iPSC-reprogramming in general. To gain more insight, here we perform a RNAi-based knockdown screen during iPSC-reprogramming of mouse fibroblasts. We discover factors important for X chromosome reactivation (XCR) and iPSC-reprogramming. Among those, we identify the cohesin complex member SMC1a as a key molecule with a specific function in XCR, as its knockdown greatly affects XCR without interfering with iPSC-reprogramming. Using super-resolution microscopy, we find SMC1a to be preferentially enriched on the active compared with the inactive X chromosome and that SMC1a is critical for the decompacted state of the active X. Specifically, depletion of SMC1a leads to contraction of the active X both in differentiated and in pluripotent cells, where it normally is in its most open state. In summary, we reveal cohesin as a key factor for remodeling of the X chromosome from an inactive to an active structure and that this is a critical step for XCR during iPSC-reprogramming.
dc.description.sponsorship This work was supported by the Spanish Agencia Estatal de Investigación (AEI) of the Ministry of Science and Innovation (PID2020-114080GB-I00 and BFU2017-86760-P (AEI/FEDER, UE) to M.P.C.; and BFU2014-55275-P, BFU2017-88407-P, EUR2019-103817, PID2021-123383NB-I00 to B.P.), the AXA Research Fund (to B.P.) and the Agencia de Gestio d’Ajuts Universitaris i de Recerca (AGAUR, 2017 SGR 689 to M.P.C. and 2017 SGR 346 to B.P.). M.P.C. is supported by ICREA (Institucio Catalana de Recerca i Estudis Avançats). We would like to thank the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) to the EMBL partnership and to the “Centro de Excelencia Severo Ochoa”. We also acknowledge support of the CERCA Programme of the Generalitat de Catalunya. M.V.N. has been supported by the People Program (Marie Curie Actions) FP7/2007–2013 under REA grant [608959] from the European Union and a Juan de la Cierva-Incorporación 2017 from the Spanish Ministry of Science and Innovation. P.A. has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 747488. M.B. has been supported by an EMBO postdoctoral fellowship (ALTF682–2021). J.T.L. is supported by the U.S. NIH grant, R01-MH118351. Portions of this work have appeared as part of the PhD dissertation “Screen for novel factors involved in pluripotency and X chromosome reactivation.“ by S.F.G. (Universitat Pompeu Fabra, 2019).
dc.format.mimetype application/pdf
dc.identifier.citation Generoso SF, Neguembor MV, Hershberg EA, Sadreyev RI, Kurimoto K, Yabuta Y, et al. Cohesin controls X chromosome structure remodeling and X-reactivation during mouse iPSC-reprogramming. Proc Natl Acad Sci USA. 2023 Jan 24;120(4):e2213810120. DOI: 10.1073/pnas.2213810120
dc.identifier.doi http://dx.doi.org/10.1073/pnas.2213810120
dc.identifier.issn 0027-8424
dc.identifier.uri http://hdl.handle.net/10230/57949
dc.language.iso eng
dc.publisher National Academy of Sciences
dc.relation.ispartof Proc Natl Acad Sci USA. 2023 Jan 24;120(4):e2213810120
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/608959
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-114080GB-I00
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BFU2017-86760-P
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2014-55275-P
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BFU2017-88407-P
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-123383NB-I00
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/747488
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.keyword X chromosome
dc.subject.keyword X-inactivation
dc.subject.keyword X-reactivation
dc.subject.keyword Cellular reprogramming
dc.subject.keyword Cohesin
dc.title Cohesin controls X chromosome structure remodeling and X-reactivation during mouse iPSC-reprogramming
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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