Transcription Factor-Directed Re-wiring of Chromatin Architecture for Somatic Cell Nuclear Reprogramming toward trans-Differentiation

Mol Cell. 2019 Nov 7;76(3):453-472.e8. doi: 10.1016/j.molcel.2019.07.036. Epub 2019 Sep 10.

Abstract

MYOD-directed fibroblast trans-differentiation into skeletal muscle provides a unique model to investigate how one transcription factor (TF) reconfigures the three-dimensional chromatin architecture to control gene expression, which is otherwise achieved by the combinatorial activities of multiple TFs. Integrative analysis of genome-wide high-resolution chromatin interactions, MYOD and CTCF DNA-binding profile, and gene expression, revealed that MYOD directs extensive re-wiring of interactions involving cis-regulatory and structural genomic elements, including promoters, enhancers, and insulated neighborhoods (INs). Re-configured INs were hot-spots of differential interactions, whereby MYOD binding to highly constrained sequences at IN boundaries and/or inside INs led to alterations of promoter-enhancer interactions to repress cell-of-origin genes and to activate muscle-specific genes. Functional evidence shows that MYOD-directed re-configuration of chromatin interactions temporally preceded the effect on gene expression and was mediated by direct MYOD-DNA binding. These data illustrate a model whereby a single TF alters multi-loop hubs to drive somatic cell trans-differentiation.

Keywords: MYOD; cell identity; chromatin organization; insulated neighborhoods; looping interactions; trans-differentiation.

Publication types

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

MeSH terms

  • Animals
  • Binding Sites
  • Cell Line
  • Cell Transdifferentiation* / genetics
  • Cellular Reprogramming*
  • Chromatin / genetics
  • Chromatin / metabolism*
  • Chromatin Assembly and Disassembly*
  • Female
  • Fibroblasts / metabolism*
  • Gene Expression Regulation, Developmental
  • Humans
  • Mice
  • Muscle Development* / genetics
  • MyoD Protein / genetics
  • MyoD Protein / metabolism*
  • Myoblasts, Skeletal / metabolism*
  • Nucleic Acid Conformation
  • Phenotype
  • Protein Binding
  • Structure-Activity Relationship
  • Transcription, Genetic

Substances

  • Chromatin
  • MyoD Protein
  • MyoD1 myogenic differentiation protein