Epigenome control by chromatin modifiers

Abstract

Chromatin is the site of numerous structural features that contribute to the regulation of the genome. Although numerous posttranslational modifications to the histone proteins that make up chromatin have been identified, it remains unclear whether and to what extent these modifications might regulate transposons and other repetitive sequences. One such modification is methylation of histone H3 lysine 4 (H3K4me), which is catalyzed by Set1 and its associated complex Set1C/COMPASS. Although H3K4me is associated with actively transcribed regions in euchromatin, an emerging body of evidence suggests that Set1-mediated transcriptional control is often repressive. This thesis work describes expanded functions for Set1C/COMPASS as a regulatory module with roles throughout the genome. We identify novel locus-dependent repressive functions for Set1 at repetitive genomic regions. Interestingly, Set1 has multiple repressive modes that are dependent and independent of H3K4me. Additionally, we show that Set1 controls the nuclear organization of Tf2 retrotransposons by antagonizing H3K4 acetylation. We describe how the roles of Set1 in the nuclear organization and transcriptional repression of Tf2 cooperate to restrict Tf2 transposition. Finally, we identify an H3K4-dependent role in countering the reduced dosage of histone H3 genes to help maintain genome stability and silencing of Tf2s and pericentromeric heterochromatin. Our study considerably expands the regulatory repertoire of an important histone modifier and highlights the multifaceted function by a highly conserved chromatin-modifying complex with diverse roles in genome control.