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Cell Stem Cell. 2017 Dec 7;21(6):834-845.e6. doi: 10.1016/j.stem.2017.11.007.

Transient and Permanent Reconfiguration of Chromatin and Transcription Factor Occupancy Drive Reprogramming.

Author information

1
Department of Anatomy and Developmental Biology, Monash University, Wellington Road, Clayton, VIC 3800, Australia; Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Wellington Road, Clayton, VIC 3800, Australia; Australian Regenerative Medicine Institute, Monash University, Wellington Road, Clayton, VIC 3800, Australia.
2
Australian Research Council Centre of Excellence in Plant Energy Biology, School of Molecular Sciences, The University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia; Harry Perkins Institute of Medical Research, 6 Verdun Street, Nedlands, WA 6009, Australia.
3
Epigenetics Research Laboratory, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; St Vincent's Clinical School, UNSW Australia, Sydney, NSW 2010, Australia.
4
Australian Research Council Centre of Excellence in Plant Energy Biology, School of Molecular Sciences, The University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia; Harry Perkins Institute of Medical Research, 6 Verdun Street, Nedlands, WA 6009, Australia. Electronic address: ryan.lister@uwa.edu.au.
5
Department of Anatomy and Developmental Biology, Monash University, Wellington Road, Clayton, VIC 3800, Australia; Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Wellington Road, Clayton, VIC 3800, Australia; Australian Regenerative Medicine Institute, Monash University, Wellington Road, Clayton, VIC 3800, Australia. Electronic address: jose.polo@monash.edu.

Abstract

Somatic cell reprogramming into induced pluripotent stem cells (iPSCs) induces changes in genome architecture reflective of the embryonic stem cell (ESC) state. However, only a small minority of cells typically transition to pluripotency, which has limited our understanding of the process. Here, we characterize the DNA regulatory landscape during reprogramming by time-course profiling of isolated sub-populations of intermediates poised to become iPSCs. Widespread reconfiguration of chromatin states and transcription factor (TF) occupancy occurs early during reprogramming, and cells that fail to reprogram partially retain their original chromatin states. A second wave of reconfiguration occurs just prior to pluripotency acquisition, where a majority of early changes revert to the somatic cell state and many of the changes that define the pluripotent state become established. Our comprehensive characterization of reprogramming-associated molecular changes broadens our understanding of this process and sheds light on how TFs access and change the chromatin during cell-fate transitions.

KEYWORDS:

ATAC-sequencing; ChIP-sequencing; DNA methylation; Oct4; Sox2; chromatin remodeling; induced pluripotent stem cells; refractory cells; reprogramming intermediates; transcriptional waves

PMID:
29220667
DOI:
10.1016/j.stem.2017.11.007
[Indexed for MEDLINE]
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