Dissecting gene activation and chromatin remodeling dynamics in single human cells undergoing reprogramming

Martínez Sarmiento, José A.; Cosma, Maria Pia; Lakadamyali, Melike

Dissecting gene activation and chromatin remodeling dynamics in single human cells undergoing reprogramming

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dc.contributor.author Martínez Sarmiento, José A.
dc.contributor.author Cosma, Maria Pia
dc.contributor.author Lakadamyali, Melike
dc.date.accessioned 2024-08-01T15:57:26Z
dc.date.available 2024-08-01T15:57:26Z
dc.date.issued 2024
dc.description.abstract During cell fate transitions, cells remodel their transcriptome, chromatin, and epigenome; however, it has been difficult to determine the temporal dynamics and cause-effect relationship between these changes at the single-cell level. Here, we employ the heterokaryon-mediated reprogramming system as a single-cell model to dissect key temporal events during early stages of pluripotency conversion using super-resolution imaging. We reveal that, following heterokaryon formation, the somatic nucleus undergoes global chromatin decompaction and removal of repressive histone modifications H3K9me3 and H3K27me3 without acquisition of active modifications H3K4me3 and H3K9ac. The pluripotency gene OCT4 (POU5F1) shows nascent and mature RNA transcription within the first 24 h after cell fusion without requiring an initial open chromatin configuration at its locus. NANOG, conversely, has significant nascent RNA transcription only at 48 h after cell fusion but, strikingly, exhibits genomic reopening early on. These findings suggest that the temporal relationship between chromatin compaction and gene activation during cellular reprogramming is gene context dependent.
dc.description.sponsorship We acknowledge Shreyasi Thakur, Peter Relich, Arian Arab, and Siewert Hugelier for help with the data analysis code. We thank Prof. Raj Jain (UPenn) and Prof. Eric Joyce (UPenn) for helpful discussions. M.L. acknowledges funding from NIH Common Fund 4D Nucleome grant U01DA052715, NIH/NIGMS grant R01 GM133842, NIH/NIAMS grant R01 AR079224, and NSF Center for Engineering Mechanobiology (CEMB) grant CMMI-1548571. M.P.C. acknowledges funding from the European Union’s Horizon 2020 Research and Innovation Program under grant agreement N 964342, Ministerio de Ciencia e Innovación BFU2017-86760-P (AEI/FEDER, UE), and an AGAUR grant from Secretaria d’Universitats i Recerca del Departament d’Empresa iConeixement de la Generalitat de Catalunya (2017 SGR 689 and 2021-SGR2021-01300), NSFC 32270577, Fundacio La Marato de TV3 202027-10. J.A.M.-S. thanks CONACYT Becas de Posgrado al Extranjero, Gobierno del Estado de Coahuila, Mexico.
dc.format.mimetype application/pdf
dc.identifier.citation Martinez-Sarmiento JA, Cosma MP, Lakadamyali M. Dissecting gene activation and chromatin remodeling dynamics in single human cells undergoing reprogramming. Cell Rep. 2024 May 28;43(5):114170. DOI: 10.1016/j.celrep.2024.114170
dc.identifier.doi http://dx.doi.org/10.1016/j.celrep.2024.114170
dc.identifier.issn 2211-1247
dc.identifier.uri http://hdl.handle.net/10230/60882
dc.language.iso eng
dc.publisher Elsevier
dc.relation.ispartof Cell Rep. 2024 May 28;43(5):114170
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/964342
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BFU2017-86760-P
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.keyword CP: Molecular biology
dc.subject.keyword CP: Stem cell research
dc.subject.keyword Nanog
dc.subject.keyword Oct4
dc.subject.keyword Cellular reprogramming
dc.subject.keyword Chromatin
dc.subject.keyword Pluripotency
dc.subject.keyword Single-molecule FISH
dc.subject.keyword Super-resolution microscopy
dc.title Dissecting gene activation and chromatin remodeling dynamics in single human cells undergoing reprogramming
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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