Abstract
Histone modifiers are critical regulators of chromatin-based processes in eukaryotes. The histone methyltransferase Set1, a component of the Set1C/COMPASS complex, catalyzes the methylation at lysine 4 of histone H3 (H3K4me), a hallmark of euchromatin. Here, we show that the fission yeast Schizosaccharomyces pombe Set1 utilizes distinct domain modules to regulate disparate classes of repetitive elements associated with euchromatin and heterochromatin via H3K4me-dependent and -independent pathways. Set1 employs its RNA-binding RRM2 and catalytic SET domains to repress Tf2 retrotransposons and pericentromeric repeats while relying on its H3K4me function to maintain transcriptional repression at the silent mating type (mat) locus and subtelomeric regions. These repressive functions of Set1 correlate with the requirement of Set1C components to maintain repression at the mat locus and subtelomeres while dispensing Set1C in repressing Tf2s and pericentromeric repeats. We show that the contributions of several Set1C subunits to the states of H3K4me diverge considerably from those of Saccharomyces cerevisiae orthologs. Moreover, unlike S. cerevisiae, the regulation of Set1 protein level is not coupled to the status of H3K4me or histone H2B ubiquitination by the HULC complex. Intriguingly, we uncover a genome organization role for Set1C and H3K4me in mediating the clustering of Tf2s into Tf bodies by antagonizing the acetyltransferase Mst1-mediated H3K4 acetylation. Our study provides unexpected insights into the regulatory intricacies of a highly conserved chromatin-modifying complex with diverse roles in genome control.
Highlights
In eukaryotic cells, DNA-based processes operate within the context of a chromatin template [1,2]
Methylation of histone H3 at lysine 4 (H3K4me) is a welldocumented mark associated with euchromatin
We investigate the contributions of the histone methyltransferase Set1 (KMT2) and its associated Set1C/ COMPASS complex in the fission yeast Schizosaccharomyces pombe to histone H3 lysine 4 methylation (H3K4me), transcriptional repression, and genome organization
Summary
DNA-based processes operate within the context of a chromatin template [1,2]. Chromatin-modifying complexes targeting select residues of histones for posttranslational modifications exert various levels of genome control including chromatin assembly, transcription, DNA repair, replication and recombination [1,3]. The roles of individual Set1C/COMPASS subunits have been revealed through studies primarily in the budding yeast Saccharomyces cerevisiae, with loss of individual subunits of Set1C having different effects on the stability of the complex and the states of H3K4me [8,9,10,11]. In budding yeast the silencing of Ty1 retrotransposons [17], long noncoding RNAs [18], and antisense regulatory noncoding RNAs [19] requires Set and H3K4me. Transcriptional profiling analysis of Set1C/COMPASS mutants supports repressive roles for H3K4me at ribosomal genes during multiple stresses [20] and for H3K4me and H3K4me through promotion of 3’end antisense transcription [21]
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