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Multifaceted genome control by Set1 Dependent and Independent of H3K4 methylation and the Set1C/COMPASS complex.

Mikheyeva IV, Grady PJ, Tamburini FB, Lorenz DR, Cam HP - PLoS Genet. (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Biology Department, Boston College, Chestnut Hill, Massachusetts, United States of America.

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.

Show MeSH
Model for the roles of Set1C in genome control in S. pombe.Set1 exerts its multifaceted genome control at euchromatin and heterochromatin dependent and independent of H3K4 methylation and the Set1C complex. At euchromatin, Set1 operates as part of the Set1C/COMPASS complex that is responsible for H3K4me distribution at active RNA polymerase II genes. At interspersed Tf2s and heterochromatic loci, Set1 has a repressive role mediated through two distinct pathways: H3K4me/Set1C-dependent repression at the silent mat locus and subtelomeres, and H3K4me/Set1C-independent repression at Tf2s and pericentromeric heterochromatin. Our findings also anticipate the presence of novel non-histone H3K4 substrates involved in the repression of Tf2s and pericentromeric repeats that could be partly mediated via Set1 association with Pol II nascent transcripts. In addition, Set1C and H3K4me have a distinct genome organization role at Tf2s by antagonizing the activity of the histone H3K4 acetyltransferase Mst1 to maintain the integrity of Tf bodies.
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pgen-1004740-g007: Model for the roles of Set1C in genome control in S. pombe.Set1 exerts its multifaceted genome control at euchromatin and heterochromatin dependent and independent of H3K4 methylation and the Set1C complex. At euchromatin, Set1 operates as part of the Set1C/COMPASS complex that is responsible for H3K4me distribution at active RNA polymerase II genes. At interspersed Tf2s and heterochromatic loci, Set1 has a repressive role mediated through two distinct pathways: H3K4me/Set1C-dependent repression at the silent mat locus and subtelomeres, and H3K4me/Set1C-independent repression at Tf2s and pericentromeric heterochromatin. Our findings also anticipate the presence of novel non-histone H3K4 substrates involved in the repression of Tf2s and pericentromeric repeats that could be partly mediated via Set1 association with Pol II nascent transcripts. In addition, Set1C and H3K4me have a distinct genome organization role at Tf2s by antagonizing the activity of the histone H3K4 acetyltransferase Mst1 to maintain the integrity of Tf bodies.

Mentions: The role of Set1 as a transcriptional repressor has been widely documented in budding yeast [17], [18], [20], [32], [46], [56], [57], [58]. However, these studies ascribed Set1 repressor function solely to H3K4me2 and/or H3K4me3 [19], [20], [21], [58]. We have previously shown that Set1 mediates repression of Tf2 retrotransposons independent of H3K4me [27]. Our current study reveals an unanticipated complexity in the repressive function of Set1, in that the requirement of H3K4me in transcriptional silencing depends upon the genomic context (Figure 7). The complete loss of H3K4me does not appear to hamper the ability of Set1 to localize to and maintain repression at Tf2s and pericentromeric repeats, while at the mat locus and subtelomeric repeats Set1-mediated H3K4me contributes to repression. These findings were consistent with analyses using Set1C subunit deletion mutants. Loci that depend on H3K4me-mediated repression (mat and subtelomeric repeats) also require Set1C components needed for maintaining proper H3K4me (all Set1C subunits except Shg1). Repression of Tf2s and pericentromeric repeats, on the other hand, is maintained in all Set1C mutants (except set1Δ).


Multifaceted genome control by Set1 Dependent and Independent of H3K4 methylation and the Set1C/COMPASS complex.

Mikheyeva IV, Grady PJ, Tamburini FB, Lorenz DR, Cam HP - PLoS Genet. (2014)

Model for the roles of Set1C in genome control in S. pombe.Set1 exerts its multifaceted genome control at euchromatin and heterochromatin dependent and independent of H3K4 methylation and the Set1C complex. At euchromatin, Set1 operates as part of the Set1C/COMPASS complex that is responsible for H3K4me distribution at active RNA polymerase II genes. At interspersed Tf2s and heterochromatic loci, Set1 has a repressive role mediated through two distinct pathways: H3K4me/Set1C-dependent repression at the silent mat locus and subtelomeres, and H3K4me/Set1C-independent repression at Tf2s and pericentromeric heterochromatin. Our findings also anticipate the presence of novel non-histone H3K4 substrates involved in the repression of Tf2s and pericentromeric repeats that could be partly mediated via Set1 association with Pol II nascent transcripts. In addition, Set1C and H3K4me have a distinct genome organization role at Tf2s by antagonizing the activity of the histone H3K4 acetyltransferase Mst1 to maintain the integrity of Tf bodies.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4214589&req=5

pgen-1004740-g007: Model for the roles of Set1C in genome control in S. pombe.Set1 exerts its multifaceted genome control at euchromatin and heterochromatin dependent and independent of H3K4 methylation and the Set1C complex. At euchromatin, Set1 operates as part of the Set1C/COMPASS complex that is responsible for H3K4me distribution at active RNA polymerase II genes. At interspersed Tf2s and heterochromatic loci, Set1 has a repressive role mediated through two distinct pathways: H3K4me/Set1C-dependent repression at the silent mat locus and subtelomeres, and H3K4me/Set1C-independent repression at Tf2s and pericentromeric heterochromatin. Our findings also anticipate the presence of novel non-histone H3K4 substrates involved in the repression of Tf2s and pericentromeric repeats that could be partly mediated via Set1 association with Pol II nascent transcripts. In addition, Set1C and H3K4me have a distinct genome organization role at Tf2s by antagonizing the activity of the histone H3K4 acetyltransferase Mst1 to maintain the integrity of Tf bodies.
Mentions: The role of Set1 as a transcriptional repressor has been widely documented in budding yeast [17], [18], [20], [32], [46], [56], [57], [58]. However, these studies ascribed Set1 repressor function solely to H3K4me2 and/or H3K4me3 [19], [20], [21], [58]. We have previously shown that Set1 mediates repression of Tf2 retrotransposons independent of H3K4me [27]. Our current study reveals an unanticipated complexity in the repressive function of Set1, in that the requirement of H3K4me in transcriptional silencing depends upon the genomic context (Figure 7). The complete loss of H3K4me does not appear to hamper the ability of Set1 to localize to and maintain repression at Tf2s and pericentromeric repeats, while at the mat locus and subtelomeric repeats Set1-mediated H3K4me contributes to repression. These findings were consistent with analyses using Set1C subunit deletion mutants. Loci that depend on H3K4me-mediated repression (mat and subtelomeric repeats) also require Set1C components needed for maintaining proper H3K4me (all Set1C subunits except Shg1). Repression of Tf2s and pericentromeric repeats, on the other hand, is maintained in all Set1C mutants (except set1Δ).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Biology Department, Boston College, Chestnut Hill, Massachusetts, United States of America.

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.

Show MeSH