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Demarcation and protection of heterochromatin domains

Partitioning into active and silent chromatin requires dedicated mechanisms that specify boundaries and maintain the identity of chromatin domains. We previously discovered a novel mechanism by which the distribution of an anti-silencing factor within heterochromatin is shaped through ubiquitin-dependent protein degradation. This mechanisms we coined ‘chromatin sculpting’ is essential for the establishment of chromatin boundaries and the protection of heterochromatin inside (Braun et al., Cell 2011). The integrity of chromatin domains can also be maintained through anchoring of factors and histone-modifying enzymes to specific chromatin regions, thereby preventing their promiscuous binding to other parts of the genome. In collaboration with Marc Bühler’s lab, we showed that the histone-methyl reader Pdp3 recruits the acetyltransferase Mst2 to euchromatin via recognition of methylated H3K36, a histone mark of actively transcribed chromatin. This anchoring mechanisms prevents Mst2 from encroaching heterochromatin and triggering a silencing defect (Flury et al., Mol Cell 2017; Georgescu et al., Microbial Cell 2020).

Heterochromatin boundary formation by ‘chromatin sculpting’. (A) The anti-silencing protein Epe1 is uniformly recruited to heterochromatin through binding to Heterochromatin Protein 1 (HP1), which recognizes methylated lysine 9 of histone H3 (H3K9me), a conserved histone mark of heterochromatin. (B) Inside heterochromatin, Epe1 is selectively modified with ubiquitin (‘ubiquitylation’) by the E3 ubiquitin ligase Cul4-Ddb1-Cdt2, which marks Epe1 for degradation by the proteasome. (C). At the heterochromatin boundaries, Epe1 is protected by an unknown mechanism from ubiquitylation and degradation, resulting in its local accumulation. Epe1 at the heterochromatin boundary prevents further spreading of H3K9me-marked heterochromatin. This ‘sculpting’ mechanism explains how Epe1 can acts as a boundary factor while it is prevented from interfering with heterochromatin inside the domain.