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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.

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Stability of Set1 proteins is uncoupled from the status of H3K4me and H2Bub.Set1 proteins containing an N-terminal FLAG epitope were analyzed by immunoblotting (IB) in cells deficient in (A) individual components of Set1C, (B) histone H3K4 mutants, or (C) HULC/H2Bub mutants. Alpha tubulin (loading control) was detected by anti-tubulin antibody (tat-1).
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pgen-1004740-g004: Stability of Set1 proteins is uncoupled from the status of H3K4me and H2Bub.Set1 proteins containing an N-terminal FLAG epitope were analyzed by immunoblotting (IB) in cells deficient in (A) individual components of Set1C, (B) histone H3K4 mutants, or (C) HULC/H2Bub mutants. Alpha tubulin (loading control) was detected by anti-tubulin antibody (tat-1).

Mentions: In budding yeast, reduced levels of Set1 proteins have been observed in mutants deficient in SWD1, SWD2, SWD3, or SPP1[10], [11], [38], [43], [44]. We examined the levels of Set1 proteins in S. pombe strains lacking each of the other Set1C components. The levels of Set1 were minimally affected by the loss of ash2, sdc1 and shg1, somewhat diminished in swd1Δ and swd3Δ, and most noticeably reduced in swd2Δ and spp1Δ mutants (Figure 4A). The loss of individual Set1C subunits on Set1 protein stability is likely to occur at the posttranslational level, as Set1 transcript levels were relatively unaffected in Set1C mutants (Figure S5).


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)

Stability of Set1 proteins is uncoupled from the status of H3K4me and H2Bub.Set1 proteins containing an N-terminal FLAG epitope were analyzed by immunoblotting (IB) in cells deficient in (A) individual components of Set1C, (B) histone H3K4 mutants, or (C) HULC/H2Bub mutants. Alpha tubulin (loading control) was detected by anti-tubulin antibody (tat-1).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4214589&req=5

pgen-1004740-g004: Stability of Set1 proteins is uncoupled from the status of H3K4me and H2Bub.Set1 proteins containing an N-terminal FLAG epitope were analyzed by immunoblotting (IB) in cells deficient in (A) individual components of Set1C, (B) histone H3K4 mutants, or (C) HULC/H2Bub mutants. Alpha tubulin (loading control) was detected by anti-tubulin antibody (tat-1).
Mentions: In budding yeast, reduced levels of Set1 proteins have been observed in mutants deficient in SWD1, SWD2, SWD3, or SPP1[10], [11], [38], [43], [44]. We examined the levels of Set1 proteins in S. pombe strains lacking each of the other Set1C components. The levels of Set1 were minimally affected by the loss of ash2, sdc1 and shg1, somewhat diminished in swd1Δ and swd3Δ, and most noticeably reduced in swd2Δ and spp1Δ mutants (Figure 4A). The loss of individual Set1C subunits on Set1 protein stability is likely to occur at the posttranslational level, as Set1 transcript levels were relatively unaffected in Set1C mutants (Figure S5).

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