A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin

TLDR

Histone lysine methylation marks distinct chromatin states, with H3‑K9 trimethylation defining mammalian pericentric heterochromatin and evolutionarily conserved H4‑K20 trimethylation—modulated by Suv4‑20 in Drosophila—acting as a key repressive mark. The authors identified two SET‑domain HMTases, Suv4‑20h1 and Suv4‑20h2, that localize to pericentric heterochromatin and trimethylate nucleosomal H4‑K20, and their interaction with HP1 isoforms implies a sequential establishment of H3‑K9 and H4‑K20 trimethylation. The study demonstrates that H4‑K20 trimethylation is focally enriched at pericentric heterochromatin, depends on prior H3.

Abstract

Histone lysine methylation is a central modification to mark functionally distinct chromatin regions. In particular, H3-K9 trimethylation has emerged as a hallmark of pericentric heterochromatin in mammals. Here we show that H4-K20 trimethylation is also focally enriched at pericentric heterochromatin. Intriguingly, H3-K9 trimethylation by the Suv39h HMTases is required for the induction of H4-K20 trimethylation, although the H4 Lys 20 position is not an intrinsic substrate for these enzymes. By using a candidate approach, we identified Suv4-20h1 and Suv4-20h2 as two novel SET domain HMTases that localize to pericentric heterochromatin and specifically act as nucleosomal H4-K20 trimethylating enzymes. Interaction of the Suv4-20h enzymes with HP1 isoforms suggests a sequential mechanism to establish H3-K9 and H4-K20 trimethylation at pericentric heterochromatin. Heterochromatic H4-K20 trimethylation is evolutionarily conserved, and in Drosophila , the Suv4-20 homolog is a novel PEV modifier to regulate position-effect variegation. Together, our data indicate a function for H4-K20 trimethylation in gene silencing and further suggest H3-K9 and H4-K20 trimethylation as important components of a repressive pathway that can index pericentric heterochromatin.