The Histone Acetyltransferase Mst2 Protects Active Chromatin from Epigenetic Silencing by Acetylating the Ubiquitin Ligase Brl1

Mol Cell. 2017 Jul 20;67(2):294-307.e9. doi: 10.1016/j.molcel.2017.05.026. Epub 2017 Jun 22.

Abstract

Faithful propagation of functionally distinct chromatin states is crucial for maintaining cellular identity, and its breakdown can lead to diseases such as cancer. Whereas mechanisms that sustain repressed states have been intensely studied, regulatory circuits that protect active chromatin from inactivating signals are not well understood. Here we report a positive feedback loop that preserves the transcription-competent state of RNA polymerase II-transcribed genes. We found that Pdp3 recruits the histone acetyltransferase Mst2 to H3K36me3-marked chromatin. Thereby, Mst2 binds to all transcriptionally active regions genome-wide. Besides acetylating histone H3K14, Mst2 also acetylates Brl1, a component of the histone H2B ubiquitin ligase complex. Brl1 acetylation increases histone H2B ubiquitination, which positively feeds back on transcription and prevents ectopic heterochromatin assembly. Our work uncovers a molecular pathway that secures epigenome integrity and highlights the importance of opposing feedback loops for the partitioning of chromatin into transcriptionally active and inactive states.

Keywords: Brl1/BRE1; Gcn5; H2B ubiquitin; H3K36me3; Mst2; RNA interference; acetylomics; epigenetic gene silencing; heterochromatin; histone modification.

MeSH terms

  • Acetylation
  • Chromatin Assembly and Disassembly*
  • Euchromatin / enzymology*
  • Euchromatin / genetics
  • Feedback, Physiological
  • Gene Expression Regulation, Fungal
  • Gene Silencing*
  • Heterochromatin / enzymology
  • Heterochromatin / genetics
  • Histone Acetyltransferases / genetics
  • Histone Acetyltransferases / metabolism*
  • Histones / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mutation
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Protein Processing, Post-Translational*
  • Schizosaccharomyces / enzymology*
  • Schizosaccharomyces / genetics
  • Schizosaccharomyces pombe Proteins / genetics
  • Schizosaccharomyces pombe Proteins / metabolism*
  • Transcription, Genetic
  • Transcriptional Activation
  • Ubiquitination

Substances

  • Brr6 protein, S pombe
  • Euchromatin
  • Heterochromatin
  • Histones
  • Membrane Proteins
  • Nuclear Proteins
  • Schizosaccharomyces pombe Proteins
  • Histone Acetyltransferases
  • Mst2 protein, S pombe