Cooperative Binding of Transcription Factors Orchestrates Reprogramming

Cell. 2017 Jan 26;168(3):442-459.e20. doi: 10.1016/j.cell.2016.12.016. Epub 2017 Jan 19.

Abstract

Oct4, Sox2, Klf4, and cMyc (OSKM) reprogram somatic cells to pluripotency. To gain a mechanistic understanding of their function, we mapped OSKM-binding, stage-specific transcription factors (TFs), and chromatin states in discrete reprogramming stages and performed loss- and gain-of-function experiments. We found that OSK predominantly bind active somatic enhancers early in reprogramming and immediately initiate their inactivation genome-wide by inducing the redistribution of somatic TFs away from somatic enhancers to sites elsewhere engaged by OSK, recruiting Hdac1, and repressing the somatic TF Fra1. Pluripotency enhancer selection is a stepwise process that also begins early in reprogramming through collaborative binding of OSK at sites with high OSK-motif density. Most pluripotency enhancers are selected later in the process and require OS and other pluripotency TFs. Somatic and pluripotency TFs modulate reprogramming efficiency when overexpressed by altering OSK targeting, somatic-enhancer inactivation, and pluripotency enhancer selection. Together, our data indicate that collaborative interactions among OSK and with stage-specific TFs direct both somatic-enhancer inactivation and pluripotency-enhancer selection to drive reprogramming.

Keywords: Klf4; Oct4; Sox2; collaborative binding; enhancers; induced pluripotent stem cells; pluripotency; reprogramming; transcription factors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cellular Reprogramming*
  • Chromatin / metabolism
  • Fibroblasts / metabolism
  • Histone Code
  • Kruppel-Like Transcription Factors / metabolism
  • Mice
  • Octamer Transcription Factor-3 / metabolism
  • Proto-Oncogene Proteins c-fos / metabolism
  • Proto-Oncogene Proteins c-myc / metabolism
  • Regulatory Elements, Transcriptional
  • SOXB1 Transcription Factors / metabolism
  • Silencer Elements, Transcriptional
  • Transcription Factors / metabolism*

Substances

  • Chromatin
  • GKLF protein
  • Kruppel-Like Transcription Factors
  • Myc protein, mouse
  • Octamer Transcription Factor-3
  • Pou5f1 protein, mouse
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-myc
  • SOXB1 Transcription Factors
  • Sox2 protein, mouse
  • Transcription Factors
  • fos-related antigen 1