Abstract
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.
Highlights
The proper segregation of active and inactive regions of the genome during differentiation is critical for the establishment and maintenance of tissue and genome integrity in eukaryotes
The loss of H3K9me compromises the transcriptional repression of tissue-specific genes and repetitive elements[6,30], no other common histone methylation marks were altered upon met-2 and set-25 ablation[7]
To understand how MET-2 is regulated, we examined in greater detail its interaction with ARLE-14 and LIN-65
Summary
The proper segregation of active and inactive regions of the genome during differentiation is critical for the establishment and maintenance of tissue and genome integrity in eukaryotes. Tissue-specific genes can be repressed by H3K9me The H3K9 histone methyltransferases (HMTs) SUV39H and SETDB1 remain bound to clusters of heterochromatin throughout the cell cycle[20,21]. In Caenorhabditis elegans, foci of MET-2, the SETDB1 homolog responsible for H3K9me deposition, and its disordered domain cofactor LIN-65, remain stable despite downregulation of the worm HP1 homologs[14]. We set out to examine what drives the focal clustering of heterochromatin proteins such as MET-2, and the relationship of such foci to histone H3K9me. The loss of H3K9me compromises the transcriptional repression of tissue-specific genes and repetitive elements[6,30], no other common histone methylation marks were altered upon met-2 and set-25 ablation[7]. MET-2 and its two cofactors, the intrinsically disordered protein LIN-65 (refs. 14,18), and the poorly characterized but conserved ARLE-14, form foci that coincide with H3K9 methylation[14,18]
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