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

Anja S. Knaupp, Sam Buckberry, Jahnvi Pflueger, Sue Mei Lim, Ethan Ford, Michael R. Larcombe, Fernando J. Rossello, Alex de Mendoza, Sara Alaei, Jaber Firas, Melissa L. Holmes, Shalima S. Nair, Susan J. Clark, Christian M. Nefzger, Ryan Lister, Jose M. Polo

Research output: Contribution to journalArticleResearchpeer-review

42 Citations (Scopus)

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. Knaupp and Buckberry et al. show that during reprogramming cells undergo major chromatin remodeling in three phases. Further, they find that Oct4 and Sox2 extensively target sites where the DNA is only accessible during the intermediate stages of reprogramming, which coincides with somatic transcription factor displacement and recruitment to those sites.

Original languageEnglish
Pages (from-to)834-845.e6
Number of pages18
JournalCell Stem Cell
Volume21
Issue number6
DOIs
Publication statusPublished - 7 Dec 2017

Keywords

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

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