SETDB1-like MET-2 promotes transcriptional silencing and development independently of its H3K9me-associated catalytic activity

Nat Struct Mol Biol. 2022 Feb;29(2):85-96. doi: 10.1038/s41594-021-00712-4. Epub 2022 Jan 31.


Transcriptionally silenced heterochromatin bearing methylation of histone H3 on lysine 9 (H3K9me) is critical for maintaining organismal viability and tissue integrity. Here we show that in addition to ensuring H3K9me, MET-2, the Caenorhabditis elegans homolog of the SETDB1 histone methyltransferase, has a noncatalytic function that contributes to gene repression. Subnuclear foci of MET-2 coincide with H3K9me deposition, yet these foci also form when MET-2 is catalytically deficient and H3K9me is compromised. Whereas met-2 deletion triggers a loss of silencing and increased histone acetylation, foci of catalytically deficient MET-2 maintain silencing of a subset of genes, blocking acetylation on H3K9 and H3K27. In normal development, this noncatalytic MET-2 activity helps to maintain fertility. Under heat stress MET-2 foci disperse, coinciding with increased acetylation and transcriptional derepression. Our study suggests that the noncatalytic, focus-forming function of this SETDB1-like protein and its intrinsically disordered cofactor LIN-61 is physiologically relevant.

Publication types

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

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Biocatalysis
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / growth & development
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Chromosomal Proteins, Non-Histone / deficiency
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism
  • Gene Silencing
  • Heterochromatin / genetics
  • Heterochromatin / metabolism
  • Histone-Lysine N-Methyltransferase / deficiency
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Histones / metabolism
  • Intrinsically Disordered Proteins / genetics
  • Intrinsically Disordered Proteins / metabolism
  • Methylation
  • Models, Biological
  • Mutation
  • Transcription, Genetic


  • Caenorhabditis elegans Proteins
  • Chromosomal Proteins, Non-Histone
  • Heterochromatin
  • Histones
  • Intrinsically Disordered Proteins
  • LIN-61 protein, C elegans
  • Histone-Lysine N-Methyltransferase
  • Met-2 protein, C elegans