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

doi:http://dx.doi.org/10.1073/pnas.2213810120

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

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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

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.