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Nat Genet. 2018 Feb;50(2):238-249. doi: 10.1038/s41588-017-0030-7. Epub 2018 Jan 15.

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

Stadhouders R1,2,3, Vidal E4,5, Serra F4,5,6, Di Stefano B4,5,7, Le Dily F4,5,6, Quilez J4,5, Gomez A4,5, Collombet S8, Berenguer C4,5, Cuartero Y4,5,6, Hecht J5,9, Filion GJ4,5, Beato M4,5, Marti-Renom MA10,11,12,13, Graf T14,15.

Author information

1
Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain. r.stadhouders@erasmusmc.nl.
2
Universitat Pompeu Fabra (UPF), Barcelona, Spain. r.stadhouders@erasmusmc.nl.
3
Department of Pulmonary Medicine, Erasmus MC, Rotterdam, the Netherlands. r.stadhouders@erasmusmc.nl.
4
Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
5
Universitat Pompeu Fabra (UPF), Barcelona, Spain.
6
Structural Genomics Group, CNAG-CRG, BIST, Barcelona, Spain.
7
Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University and Harvard Medical School, Cambridge, MA, USA.
8
Institut de Biologie de l'Ecole Normale Supérieure (IBENS), CNRS UMR8197, INSERM U1024, Paris, France.
9
Genomics Unit, CRG, BIST, Barcelona, Spain.
10
Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain. martirenom@cnag.crg.eu.
11
Universitat Pompeu Fabra (UPF), Barcelona, Spain. martirenom@cnag.crg.eu.
12
Structural Genomics Group, CNAG-CRG, BIST, Barcelona, Spain. martirenom@cnag.crg.eu.
13
Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. martirenom@cnag.crg.eu.
14
Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain. thomas.graf@crg.eu.
15
Universitat Pompeu Fabra (UPF), Barcelona, Spain. thomas.graf@crg.eu.

Abstract

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.

PMID:
29335546
PMCID:
PMC5810905
DOI:
10.1038/s41588-017-0030-7
[Indexed for MEDLINE]
Free PMC Article

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