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

Qian Yi Lee, Moritz Mall, Soham Chanda, Bo Zhou, Kylesh S. Sharma, Katie Schaukowitch, Juan M. Adrian-Segarra, Sarah D. Grieder, Michael S. Kareta, Orly L. Wapinski, Cheen Euong Ang, Rui Li, Thomas C. Südhof, Howard Y. Chang, Marius Wernig

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)401-411
Number of pages11
JournalNature Cell Biology
Volume22
Issue number4
DOIs
StatePublished - Apr 1 2020

ASJC Scopus subject areas

  • Cell Biology

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