Pro-neuronal activity of Myod1 due to promiscuous binding to neuronal genes

Nat Cell Biol. 2020 Apr;22(4):401-411. doi: 10.1038/s41556-020-0490-3. Epub 2020 Mar 30.

Abstract

The on-target pioneer factors Ascl1 and Myod1 are sequence-related but induce two developmentally unrelated lineages-that is, neuronal and muscle identities, respectively. It is unclear how these two basic helix-loop-helix (bHLH) factors mediate such fundamentally different outcomes. The chromatin binding of Ascl1 and Myod1 was surprisingly similar in fibroblasts, yet their transcriptional outputs were drastically different. We found that quantitative binding differences explained differential chromatin remodelling and gene activation. Although strong Ascl1 binding was exclusively associated with bHLH motifs, strong Myod1-binding sites were co-enriched with non-bHLH motifs, possibly explaining why Ascl1 is less context dependent. Finally, we observed that promiscuous binding of Myod1 to neuronal targets results in neuronal reprogramming when the muscle program is inhibited by Myt1l. Our findings suggest that chromatin access of on-target pioneer factors is primarily driven by the protein-DNA interaction, unlike ordinary context-dependent transcription factors, and that promiscuous transcription factor binding requires specific silencing mechanisms to ensure lineage fidelity.

Publication types

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

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Binding Sites
  • Cell Lineage / genetics
  • Cellular Reprogramming
  • Chromatin / chemistry
  • Chromatin / metabolism
  • Embryo, Mammalian
  • Fibroblasts / cytology
  • Fibroblasts / metabolism*
  • Gene Expression Regulation, Developmental*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • MyoD Protein / genetics*
  • MyoD Protein / metabolism
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Neurons / cytology
  • Neurons / metabolism*
  • Nucleotide Motifs
  • Protein Binding
  • Signal Transduction
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transcription, Genetic

Substances

  • Ascl1 protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Chromatin
  • MyoD Protein
  • MyoD1 myogenic differentiation protein
  • Myt1l protein, mouse
  • Nerve Tissue Proteins
  • Transcription Factors