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

• Published in: Nature structural & molecular biology Vol. 29; no. 2; pp. 85 - 96
• Main Authors: Delaney, Colin E., Methot, Stephen P., Kalck, Veronique, Seebacher, Jan, Hess, Daniel, Gasser, Susan M., Padeken, Jan
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2022; Nature Publishing Group
• Subjects: 14/63; 45/15; 45/91; 631/208/176/2016; 631/208/177; 82/58; Acetylation; Animals; Animals, Genetically Modified; Biocatalysis; Biochemistry; Biological Microscopy; Biomedical and Life Sciences; Caenorhabditis elegans - genetics; Caenorhabditis elegans - growth & development; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Catalytic activity; Chromosomal Proteins, Non-Histone - deficiency; Chromosomal Proteins, Non-Histone - genetics; Chromosomal Proteins, Non-Histone - metabolism; Derepression; Fertility; Gene Silencing; Genetic analysis; Genomes; Heat stress; Heat tolerance; Heterochromatin; Heterochromatin - genetics; Heterochromatin - metabolism; Histone H3; Histone methyltransferase; Histone-Lysine N-Methyltransferase - deficiency; Histone-Lysine N-Methyltransferase - genetics; Histone-Lysine N-Methyltransferase - metabolism; Histones; Histones - metabolism; Homology; Intrinsically Disordered Proteins - genetics; Intrinsically Disordered Proteins - metabolism; Life Sciences; Lysine; Membrane Biology; Methylation; Models, Biological; Mutation; Protein Structure; Transcription, Genetic
• ISSN: 1545-9993; 1545-9985
• DOI: 10.1038/s41594-021-00712-4

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-65 is physiologically relevant. Genetic and genome-wide analysis of a catalytically deficient SETDB1-like enzyme, MET-2, in C aenorhabditis elegans reveals that MET-2 promotes transcriptional silencing and fertility through both H3K9 methylation and focus formation, which blocks histone acetylation.