Transcription factors orchestrate dynamic interplay between genome topology and gene regulation during cell reprogramming

Chromosomal architecture is known to influence gene expression, yet its role in controlling cell fate remains poorly understood. Reprogramming of somatic cells into pluripotent stem cells (PSCs) by the transcription factors (TFs) OCT4, SOX2, KLF4 and MYC offers an opportunity to address this questio...

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Detalles Bibliográficos
Autores: Stadhouders, Ralph, Vidal Ocabo, Enrique, Serra, François, Di Stefano, Bruno, 1984-, Le Dily, François, Quilez Oliete, Javier, Gómez, Antonio, Collombet, Samuel, Berenguer Balaguer, Clara, Cuartero, Yasmina, Hecht, Jochen, Filion, Guillaume, Beato, Miguel, Martí Renom, Marc A., Graf, T. (Thomas)
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2018
País:España
Institución:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/34895
Acceso en línea:http://hdl.handle.net/10230/34895
http://dx.doi.org/10.1038/s41588-017-0030-7
Access Level:acceso abierto
Palabra clave:Gene expression regulation
Cellular reprogramming
Induced pluripotent stem cells
Diploid cell
Klf4 gene
Descripción
Sumario:Chromosomal architecture is known to influence gene expression, yet its role in controlling cell fate remains poorly understood. Reprogramming of somatic cells into pluripotent stem cells (PSCs) by the transcription factors (TFs) OCT4, SOX2, KLF4 and MYC offers an opportunity to address this question but is severely limited by the low proportion of responding cells. We have recently developed a highly efficient reprogramming protocol that synchronously converts somatic into pluripotent stem cells. Here, we used this system to integrate time-resolved changes in genome topology with gene expression, TF binding and chromatin-state dynamics. The results showed that TFs drive topological genome reorganization at multiple architectural levels, often before changes in gene expression. Removal of locus-specific topological barriers can explain why pluripotency genes are activated sequentially, instead of simultaneously, during reprogramming. Together, our results implicate genome topology as an instructive force for implementing transcriptional programs and cell fate in mammals.

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