Generoso, Serena Francesca, 1988-Neguembor, Maria VictoriaHershberg, Elliot A.Sadreyev, Ruslan IlyasovichKurimoto, KazukiYabuta, YukihiroRicci, RaffaeleAudergon, PaulineBauer, Moritz, 1987-Saitou, MitinoriHochedlinger, KonradBeliveau, Brian J.Cosma, Maria PiaLee, Jeannie T.Payer, Bernhard2023-09-262023-09-262023Generoso 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.22138101200027-8424http://hdl.handle.net/10230/57949Reactivation 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.application/pdfeng© 2023 the Author(s). Published by PNAS. This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).info:eu-repo/semantics/articlehttp://dx.doi.org/10.1073/pnas.2213810120X chromosomeX-inactivationX-reactivationCellular reprogrammingCohesininfo:eu-repo/semantics/openAccess