Transcription profiling by array of fission yeast mutants of the Set1/Compass complex under steady-state and dynamic conditions to analyze the role of histone 3 lysine 4 methylation in transcription
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ABSTRACT:
ORGANISM(S): Saccharomyces cerevisiae
SUBMITTER: Thanasis Margaritis
PROVIDER: E-TABM-486 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:The stimulation of trimethylation of histone H3 lysine 4 (H3K4) by H2B monoubiquitination (H2Bub) has been widely studied with multiple mechanisms proposed for this form of histone crosstalk. Cps35/Swd2 within COMPASS is considered to bridge these processes. However, a truncated form of Set1 (762-Set1) is reported to function in H3K4 trimethylation without interacting with Cps35/Swd2, and such crosstalk is attributed to the n-SET domain of Set1 and its interaction with the Cps40/Spp1 subunit of COMPASS. Here, we use biochemical, structural, in vivo, and ChIP-seq approaches to demonstrate that Cps40/Spp1 and the n-SET domain of Set1 are required for the stability of Set1 and not the crosstalk. Furthermore, the apparent wild-type levels of H3K4 trimethylation (H3K4me3) in the 762-Set1 strain is due to rogue methylase activity of this mutant resulting in the mislocalization of H3K4me3 from the promoter-proximal regions to gene bodies and intergenic regions. We have also performed detailed screens and identified yeast strains lacking H2Bub, but containing intact H2Bub enzymes, that have normal levels of H3K4me3, suggesting that ubiquitination may not directly stimulate COMPASS, but rather works in a context of the PAF and Rad6/Bre1 complexes. Our study demonstrates that the ubiquitination machinery and Cps35/Swd2 function to focus COMPASS’ H3K4me3 activity at promoter-proximal regions in a context dependent manner. ChIP-Seq for H3K4ME3 in S. cerevisie wild-type strains and strains expressing a truncated form of Set1: aa762-1080 Set1. H3K4ME3 ChIP-Seq was also compared for wild-type, leo1 knockout, and chd1 knockout strains
2014-01-09 | E-GEOD-53241 | biostudies-arrayexpress
Project description:The stimulation of trimethylation of histone H3 lysine 4 (H3K4) by H2B monoubiquitination (H2Bub) has been widely studied with multiple mechanisms proposed for this form of histone crosstalk. Cps35/Swd2 within COMPASS is considered to bridge these processes. However, a truncated form of Set1 (762-Set1) is reported to function in H3K4 trimethylation without interacting with Cps35/Swd2, and such crosstalk is attributed to the n-SET domain of Set1 and its interaction with the Cps40/Spp1 subunit of COMPASS. Here, we use biochemical, structural, in vivo, and ChIP-seq approaches to demonstrate that Cps40/Spp1 and the n-SET domain of Set1 are required for the stability of Set1 and not the crosstalk. Furthermore, the apparent wild-type levels of H3K4 trimethylation (H3K4me3) in the 762-Set1 strain is due to rogue methylase activity of this mutant resulting in the mislocalization of H3K4me3 from the promoter-proximal regions to gene bodies and intergenic regions. We have also performed detailed screens and identified yeast strains lacking H2Bub, but containing intact H2Bub enzymes, that have normal levels of H3K4me3, suggesting that ubiquitination may not directly stimulate COMPASS, but rather works in a context of the PAF and Rad6/Bre1 complexes. Our study demonstrates that the ubiquitination machinery and Cps35/Swd2 function to focus COMPASS’ H3K4me3 activity at promoter-proximal regions in a context dependent manner.
2014-01-09 | GSE53241 | GEO
Project description:TET proteins convert 5-methylcytosine to 5-hydroxymethylcytosine, an emerging dynamic epigenetic state of DNA that can influence transcription. Evidence has linked TET1 function to epigenetic repression complexes, yet mechanistic information, especially for the TET2 and TET3 proteins, remains limited. Here, we show a direct interaction of TET2 and TET3 with O-GlcNAc transferase (OGT). OGT does not appear to influence hmC activity, rather TET2 and TET3 promote OGT activity. TET2/3-OGT co-localize on chromatin at active promoters enriched for H3K4me3 and reduction of either TET2/3 or OGT activity results in a direct decrease in H3K4me3 and concomitant decreased transcription. Further, we show that Host Cell Factor 1 (HCF1), a component of the H3K4 methyltransferase SET1/COMPASS complex, is a specific GlcNAcylation target of TET2/3-OGT, and modification of HCF1 is important for the integrity of SET1/COMPASS. Additionally, we find both TET proteins and OGT activity promote binding of the SET1/COMPASS H3K4 methyltransferase, SETD1A, to chromatin. Finally, studies in Tet2 knockout mouse bone marrow tissue extend and support the data as decreases are observed of global GlcNAcylation and also of H3K4me3, notably at several key regulators of haematopoiesis. Together, our results unveil a step-wise model, involving TET-OGT interactions, promotion of GlcNAcylation, and influence on H3K4me3 via SET1/COMPASS, highlighting a novel means by which TETs may induce transcriptional activation. ChIP-Seq experiments were performed on Illumina HiScanSQ sequencer in wild-type HEK293T cells for H3K4me3 histone marks, O-GlcNAc and HCF1, for HT-TET2, HT-TET3 and HT-OGT in HEK293T cells overexpressing those three fusion proteins and in TET2 Kd HEK293T cells for H3K4me3 histone marks. ChIP-Seqs were also performed in mouse bone marrow tissues for H3K4me3 histone marks, O-GlcNAc, endogenous Tet2 and in Tet2 Ko bone marrow tissues for H3K4me3 histone marks.
2013-02-07 | E-GEOD-36620 | biostudies-arrayexpress
Project description:Changes in histone post-translational modifications are associated with aging through poorly defined mechanisms. Histone 3 lysine 4 (H3K4) methylation at promoters is deposited by SET1 family methyltransferases acting within conserved multiprotein complexes known as COMPASS. Using co-immunopurification coupled to mass spectrometry-based proteomics, we characterized complex members and binding partners in various genetic contexts, using WDR-5 or CFP-1 proteins as baits.
2021-12-08 | PXD029904 | Pride
Project description:Methylation of histone H3 lysine 4 (H3K4) by the Set1/COMPASS complex is coupled with active transcription, and this modification is important for regulating gene expression. Set1/COMPASS associates with the RNA polymerase II (RNApII) C-terminal domain (CTD) to establish proper levels and distribution of H3K4 methylations.To ask how the Set1-RNApII CTD binding affects the occupancy and overall level of H3K4 methylations, ChIP-Seq was pefromed in cells transformed with full length or N-terminal truncated Set1. Our results indicate that Set1-RNApII CTD interaction is necessary for maintaining H3K4 methylations throughout the genes.
2019-10-02 | GSE138281 | GEO
Project description:TET proteins convert 5-methylcytosine to 5-hydroxymethylcytosine, an emerging dynamic epigenetic state of DNA that can influence transcription. Evidence has linked TET1 function to epigenetic repression complexes, yet mechanistic information, especially for the TET2 and TET3 proteins, remains limited. Here, we show a direct interaction of TET2 and TET3 with O-GlcNAc transferase (OGT). OGT does not appear to influence hmC activity, rather TET2 and TET3 promote OGT activity. TET2/3-OGT co-localize on chromatin at active promoters enriched for H3K4me3 and reduction of either TET2/3 or OGT activity results in a direct decrease in H3K4me3 and concomitant decreased transcription. Further, we show that Host Cell Factor 1 (HCF1), a component of the H3K4 methyltransferase SET1/COMPASS complex, is a specific GlcNAcylation target of TET2/3-OGT, and modification of HCF1 is important for the integrity of SET1/COMPASS. Additionally, we find both TET proteins and OGT activity promote binding of the SET1/COMPASS H3K4 methyltransferase, SETD1A, to chromatin. Finally, studies in Tet2 knockout mouse bone marrow tissue extend and support the data as decreases are observed of global GlcNAcylation and also of H3K4me3, notably at several key regulators of haematopoiesis. Together, our results unveil a step-wise model, involving TET-OGT interactions, promotion of GlcNAcylation, and influence on H3K4me3 via SET1/COMPASS, highlighting a novel means by which TETs may induce transcriptional activation.
2013-02-07 | GSE36620 | GEO
Project description:H3K4 methylation is a conserved histone modification crucial for gene regulation, yet the post-translational modifications of the Set1-COMPASS complex remain largely unexplored. This study elucidates the significance of N-terminal acetylation in modulating H3K4 methylation patterns. Firstly, loss of NatA complex resulted in a significant decrease in H3K4me3 levels and a shift of H3K4me2 from 5' transcribed regions to promoters. Importantly, NatA physically interacted with the Set1-COMPASS complex and facilitated N-terminal acetylation of the Shg1 subunit. Surprisingly, deletion of SHG1 or mutation of the acetylation site (A2P) in Shg1 led to reduced H3K4 methylation in cells lacking Spp1. Additionally, NatB complex also contributed to H3K4 methylation regulation, potentially through N-terminal acetylation of Swd1. These findings highlight the novel role of N-terminal acetylation in fine-tuning the function of the Set1-COMPASS complex and shaping H3K4 methylation patterns. This study sheds light on the intricate regulation of H3K4 methylation and emphasizes the significance of N-terminal acetylation as a regulatory mechanism in this process.
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Project description:This study investigated the role Complex of Proteins Associated with Set1 (COMPASS) in heart development. These are evolutionarily highly conserved multiprotein complexes required for H3K4 methylation. In Drosophila, their core subunits are Set1, Trx, and Trr. We studied flies deficient for either of these three subunits their hearts. These flies showed high lethality at eclosion (emergence of adult flies from their pupal case) and significantly shortened lifespans for the adults that did emerge. Furthermore, their hearts showed reduced H3K4 monomethylation (H3K4me1) and dimethylation (H3K4me2), and significantly altered gene expression patterns. The data revealed that each of the COMPASS core subunits (Set1, Trx, and Trr) control methylation of different sets of genes with distinct temporal activity: Set1 throughout, whereas Trr was active early and Trx at later stages of heart development. We found that many metabolic pathways were active early in development and throughout, while muscle and heart differentiation processes were methylated during later stages of development. Taken together, the findings demonstrate the importance of COMPASS complexes during heart development, therewith supporting their implication in congenital heart diseases.
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Project description:H3K4 methylation is a conserved histone modification crucial for gene regulation, yet the post-translational modifications of the Set1-COMPASS complex remain largely unexplored. This study elucidates the significance of N-terminal acetylation in modulating H3K4 methylation patterns. Firstly, loss of NatA complex resulted in a significant decrease in H3K4me3 levels and a shift of H3K4me2 from 5' transcribed regions to promoters. Importantly, NatA physically interacted with the Set1-COMPASS complex and facilitated N-terminal acetylation of the Shg1 subunit. Surprisingly, deletion of SHG1 or mutation of the acetylation site (A2P) in Shg1 led to reduced H3K4 methylation in cells lacking Spp1. Additionally, NatB complex also contributed to H3K4 methylation regulation, potentially through N-terminal acetylation of Swd1. These findings highlight the novel role of N-terminal acetylation in fine-tuning the function of the Set1-COMPASS complex and shaping H3K4 methylation patterns. This study sheds light on the intricate regulation of H3K4 methylation and emphasizes the significance of N-terminal acetylation as a regulatory mechanism in this process.
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Project description:H3K4 methylation is a conserved histone modification crucial for gene regulation, yet the post-translational modifications of the Set1-COMPASS complex remain largely unexplored. This study elucidates the significance of N-terminal acetylation in modulating H3K4 methylation patterns. Firstly, loss of NatA complex resulted in a significant decrease in H3K4me3 levels and a shift of H3K4me2 from 5' transcribed regions to promoters. Importantly, NatA physically interacted with the Set1-COMPASS complex and facilitated N-terminal acetylation of the Shg1 subunit. Surprisingly, deletion of SHG1 or mutation of the acetylation site (A2P) in Shg1 led to reduced H3K4 methylation in cells lacking Spp1. Additionally, NatB complex also contributed to H3K4 methylation regulation, potentially through N-terminal acetylation of Swd1. These findings highlight the novel role of N-terminal acetylation in fine-tuning the function of the Set1-COMPASS complex and shaping H3K4 methylation patterns. This study sheds light on the intricate regulation of H3K4 methylation and emphasizes the significance of N-terminal acetylation as a regulatory mechanism in this process.
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