H3K9me selectively blocks transcription factor activity and ensures differentiated tissue integrity

Nat Cell Biol. 2021 Nov;23(11):1163-1175. doi: 10.1038/s41556-021-00776-w. Epub 2021 Nov 4.


The developmental role of histone H3K9 methylation (H3K9me), which typifies heterochromatin, remains unclear. In Caenorhabditis elegans, loss of H3K9me leads to a highly divergent upregulation of genes with tissue and developmental-stage specificity. During development H3K9me is lost from differentiated cell type-specific genes and gained at genes expressed in earlier developmental stages or other tissues. The continuous deposition of H3K9me2 by the SETDB1 homolog MET-2 after terminal differentiation is necessary to maintain repression. In differentiated tissues, H3K9me ensures silencing by restricting the activity of a defined set of transcription factors at promoters and enhancers. Increased chromatin accessibility following the loss of H3K9me is neither sufficient nor necessary to drive transcription. Increased ATAC-seq signal and gene expression correlate at a subset of loci positioned away from the nuclear envelope, while derepressed genes at the nuclear periphery remain poorly accessible despite being transcribed. In conclusion, H3K9me deposition can confer tissue-specific gene expression and maintain the integrity of terminally differentiated muscle by restricting transcription factor activity.

Publication types

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

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Binding Sites
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Cell Differentiation*
  • Chromatin Assembly and Disassembly*
  • Chromatin Immunoprecipitation Sequencing
  • Gene Expression Profiling
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Histones / genetics
  • Histones / metabolism*
  • Methylation
  • Protein Binding
  • Protein Processing, Post-Translational*
  • Time Factors
  • Transcription, Genetic*
  • Transcriptome


  • Caenorhabditis elegans Proteins
  • Histones
  • Histone-Lysine N-Methyltransferase
  • Met-2 protein, C elegans