Chromatin Accessibility Dynamics during iPSC Reprogramming

Cell Stem Cell. 2017 Dec 7;21(6):819-833.e6. doi: 10.1016/j.stem.2017.10.012.

Abstract

Cell-fate decisions remain poorly understood at the chromatin level. Here, we map chromatin remodeling dynamics during induction of pluripotent stem cells. ATAC-seq profiling of MEFs expressing Oct4-Sox2-Klf4 (OSK) reveals dynamic changes in chromatin states shifting from open to closed (OC) and closed to open (CO), with an initial burst of OC and an ending surge of CO. The OC loci are largely composed of genes associated with a somatic fate, while the CO loci are associated with pluripotency. Factors/conditions known to impede reprogramming prevent OSK-driven OC and skew OC-CO dynamics. While the CO loci are enriched for OSK motifs, the OC loci are not, suggesting alternative mechanisms for chromatin closing. Sap30, a Sin3A corepressor complex component, is required for the OC shift and facilitates reduced H3K27ac deposition at OC loci. These results reveal a chromatin accessibility logic during reprogramming that may apply to other cell-fate decisions.

Keywords: Sap30; binary logic; chromatin dynamics; open/close; reprogramming.

MeSH terms

  • Animals
  • Cells, Cultured
  • Cellular Reprogramming*
  • Chromatin / genetics
  • Chromatin / metabolism*
  • Induced Pluripotent Stem Cells / cytology*
  • Induced Pluripotent Stem Cells / metabolism*
  • Kruppel-Like Factor 4
  • Kruppel-Like Transcription Factors / metabolism
  • Mice
  • Octamer Transcription Factor-3 / metabolism
  • SOXB1 Transcription Factors / metabolism

Substances

  • Chromatin
  • Klf4 protein, mouse
  • Kruppel-Like Factor 4
  • Kruppel-Like Transcription Factors
  • Octamer Transcription Factor-3
  • Pou5f1 protein, mouse
  • SOXB1 Transcription Factors
  • Sox2 protein, mouse