HPL-2/HP1 and MET-2/SETDB1 bind distinct co-factors that promote heterochromatic foci, gene repression and organogenesis independently of H3K9 methylation.

In differentiated cells, genome segregation into heterochromatin and euchromatin is mediated by modified histones, which recruit so-called reader proteins. Surprisingly, many histone modifiers remain functional in the absence of catalytic activity, but the underlying mechanism remains unclear. To explore this puzzle, we examined the relationship between C. elegans MET-2/SETDB1, a histone H3 lysine (H3K9me) methyltransferase that also has non-catalytic roles, and the canonical H3K9me reader HPL-2 (HP1). We show that HPL-2 represses transcription and supports organogenesis independently of H3K9me binding, whereas complete loss of met-2 and hpl-2 causes severe transcriptional and developmental defects. MET-2 and HPL-2 rely on different binding partners - the disordered protein LIN-65/ATF7IP and the multi-zinc finger protein LIN-13, respectively - for localization and function. The results suggest that HPL-2 can operate through alternative protein interactions, and that HPL-2 and MET-2 function in parallel, H3K9me-independent pathways, with H3K9me acting as a reinforcing but non-essential contributor to these processes.