Signal-induced enhancer activation requires Ku70 to read topoisomerase1-DNA covalent complexes

Nat Struct Mol Biol. 2023 Feb;30(2):148-158. doi: 10.1038/s41594-022-00883-8. Epub 2023 Feb 6.

Abstract

Enhancer activation serves as the main mechanism regulating signal-dependent transcriptional programs, ensuring cellular plasticity, yet central questions persist regarding their mechanism of activation. Here, by successfully mapping topoisomerase I-DNA covalent complexes genome-wide, we find that most, if not all, acutely activated enhancers, including those induced by 17β-estradiol, dihydrotestosterone, tumor necrosis factor alpha and neuronal depolarization, are hotspots for topoisomerase I-DNA covalent complexes, functioning as epigenomic signatures read by the classic DNA damage sensor protein, Ku70. Ku70 in turn nucleates a heterochromatin protein 1 gamma (HP1γ)-mediator subunit Med26 complex to facilitate acute, but not chronic, transcriptional activation programs. Together, our data uncover a broad, unappreciated transcriptional code, required for most, if not all, acute signal-dependent enhancer activation events in both mitotic and postmitotic cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • DNA
  • DNA Topoisomerases, Type I* / metabolism
  • Enhancer Elements, Genetic*
  • Ku Autoantigen / metabolism
  • Transcription Factors / metabolism
  • Transcriptional Activation

Substances

  • DNA
  • DNA Topoisomerases, Type I
  • Transcription Factors
  • Ku Autoantigen