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HP1 can act independently of H3K9 methylation to promote heterochromatin focus formation, gene repression, and organogenesis [CUT&Tag]

ABSTRACT: Histone post-translational modifications (PTMs) segregate genomes into heterochromatin and euchromatin by recruiting readers, including HP1 proteins that bind H3 lysine 9 methylation (H3K9me). Here, we report H3K9me-independent functions for the HP1 orthologue HPL-2 and the H3K9 methyltransferase MET-2/SETDB1 in C. elegans. Both proteins co-localize in H3K9me-containing sub-nuclear foci independently. Their combined loss additively disrupts gene repression and organogenesis. HPL-2 remains functional in the absence of H3K9me: HPL-2 deficient for H3K9me-binding still localizes to heterochromatin foci, restricts cell fate decisions and represses developmental genes. MET-2, catalytically active or not, requires the disordered protein LIN-65 to form foci and silence genes in vivo, while HPL-2 requires a multi-zinc finger ligand, LIN-13. Molecular dynamics simulations and in vitro assays suggest that these cofactor-driven condensate assemblies underlie the H3K9me-independent formation of heterochromatic foci in vivo. We define parallel, H3K9me-independent pathways through which MET-2 and HPL-2 can repress genes essential for organogenesis, reinforcing H3K9me-dependent mechanisms.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE345142 | GEO | 2026/08/31

REPOSITORIES: GEO

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