The euchromatic histone mark H3K36me3 preserves heterochromatin through maintaining the integrity of chromatin domains

CAPELLA, MATIAS; GEORGESCU, PAULA R; FISCHER-BURKART, SABINE; BRAUN, SIGURD

Barcelona

Workshop; EMBO Workshop on fission yeast; 2019

European Molecular Biology Organization

Maintaining the identity of chromatin states requires mechanisms ensuring their structural integrity through the concerted actions of histone modifiers, readers, and erasers. Histone H3K9me and H3K27me are hallmarks of repressed chromatin, whereas H3K4me and H3K36me are associated with euchromatin. Paradoxically, several studies have reported that loss of Set2, the methyltransferase responsible for H3K36me, causes de-repression of heterochromatin.We previously showed that the acetyltransferase Mst2C is recruited to H3K36me3 via its PWWP domain-containing subunit Pdp3 [1]. Anchoring Mst2C to chromatin mediates acetylation of the ubiquitin ligase Brl1 and promotes H2B ubiquitylation, thereby protecting euchromatin from ectopic heterochromatin assembly. Conversely, loss of Pdp3 results in the dissociation of Mst2C from euchromatin and its invasion into heterochromatin. Here we show that delocalization of Mst2C is the main cause of the silencing defects observed in Set2-deficient cells. While combining set2 and pdp3 deletions result in an epistatic phenotype, deletion of Mst2 fully restores silencing in set2 cells. Suppression of the set2∆ silencing defect is specific for pericentromeres and subtelomeres marked by H3K9me but not seen for loci that lack genuine heterochromatin. Moreover, unlike at euchromatin, the role of Mst2 in silencing is independent of Brl1 acetylation. Since Mst2 acts redundantly with Gcn5 in H3K14ac, we suspect that it targets another, yet unknown substrate critical for heterochromatin silencing. Our findings demonstrate that maintenance of chromatin states requires spatial constraint of opposing chromatin activities.References[1] V. Flury, P.R. Georgescu, V. Iesmantavicius, Y. Shimada, T. Kuzdere, S. Braun, M. Bühler, Mol. Cell, 2017, 67, 294?307.e9