Benomyl toxicity links histone H3 lysine 4 methylation to cell cycle control
Ontology highlight
ABSTRACT:
ORGANISM(S): Saccharomyces cerevisiae
PROVIDER: GSE83162 | GEO | 2017/03/01
SECONDARY ACCESSION(S): PRJNA325282
REPOSITORIES: GEO
Similar Datasets
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:UnlabelledNumerous studies in multiple systems support that histone H3 lysine 36 dimethylation (H3K36me2) is associated with transcriptional activation; however, the underlying mechanisms are not well defined. Here, we show that the H3K36me2 chromatin mark written by the ASH1L histone methyltransferase is preferentially bound in vivo by LEDGF, a mixed-lineage leukemia (MLL)-associated protein that colocalizes with MLL, ASH1L, and H3K36me2 on chromatin genome wide. Furthermore, ASH1L facilitates recruitment of LEDGF and wild-type MLL proteins to chromatin at key leukemia target genes and is a crucial regulator of MLL-dependent transcription and leukemic transformation. Conversely, KDM2A, an H3K36me2 demethylase and Polycomb group silencing protein, antagonizes MLL-associated leukemogenesis. Our studies are the first to provide a basic mechanistic insight into epigenetic interactions wherein placement, interpretation, and removal of H3K36me2 contribute to the regulation of gene expression and MLL leukemia, and suggest ASH1L as a novel target for therapeutic intervention.SignificanceEpigenetic regulators play vital roles in cancer pathogenesis and represent a new frontier in therapeutic targeting. Our studies provide basic mechanistic insight into the role of H3K36me2 in transcription activation and MLL leukemia pathogenesis and implicate ASH1L histone methyltransferase as a promising target for novel molecular therapy. Cancer Discov; 6(7); 770-83. ©2016 AACR.See related commentary by Balbach and Orkin, p. 700This article is highlighted in the In This Issue feature, p. 681.
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Project description:Methylation of histone H3 lysine 4 (H3K4me) is an evolutionarily conserved modification whose role in the regulation of gene expression has been extensively studied. In contrast, the function of H3K4 acetylation (H3K4ac) has received little attention because of a lack of tools to separate its function from that of H3K4me. Here we show that, in addition to being methylated, H3K4 is also acetylated in budding yeast. Genetic studies reveal that the histone acetyltransferases (HATs) Gcn5 and Rtt109 contribute to H3K4 acetylation in vivo. Whilst removal of H3K4ac from euchromatin mainly requires the histone deacetylase (HDAC) Hst1, Sir2 is needed for H3K4 deacetylation in heterochomatin. Using genome-wide chromatin immunoprecipitation (ChIP), we show that H3K4ac is enriched at promoters of actively transcribed genes and located just upstream of H3K4 tri-methylation (H3K4me3), a pattern that has been conserved in human cells. We find that the Set1-containing complex (COMPASS), which promotes H3K4me2 and -me3, also serves to limit the abundance of H3K4ac at gene promoters. In addition, we identify a group of genes that have high levels of H3K4ac in their promoters and are inadequately expressed in H3-K4R, but not in set1 mutant strains suggesting that H3K4ac plays a positive role in transcription. Our results reveal a novel regulatory feature of promoter-proximal chromatin, involving mutually exclusive histone modifications of the same histone residue (H3K4ac and H3K4me).
2011-02-15 | GSE27307 | GEO
Project description:The histone lysine methyltransferase NSD2 (MMSET/WHSC1) is implicated in diverse diseases and commonly overexpressed in multiple myeloma due to a recurrent t(4;14) chromosomal translocation. However, the precise catalytic activity of NSD2 is obscure, preventing progress in understanding how this enzyme influences chromatin biology and myeloma pathogenesis. Here, we show that dimethylation of histone H3 at lysine 36 (H3K36me2) is the principal chromatin-regulatory activity of NSD2. Catalysis of H3K36me2 by NSD2 is sufficient for gene activation. In t(4;14)-positive myeloma cells, the normal genome-wide and gene-specific distribution of H3K36me2 is obliterated, creating a chromatin landscape that selects for a transcription profile favorable for myelomagenesis. Catalytically active NSD2 confers xenograft tumor formation upon t(4;14)-negative cells and promotes oncogenic transformation of primary cells in an H3K36me2-dependent manner. Together, our findings establish H3K36me2 as the primary product generated by NSD2 and demonstrate that genomic disorganization of this canonical chromatin mark by NSD2 initiates oncogenic programming.
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Project description:Dynamic regulation of diverse nuclear processes is intimately linked to covalent modifications of chromatin. Much attention has focused on methylation at lysine 4 of histone H3 (H3K4), owing to its association with euchromatic genomic regions. H3K4 can be mono-, di- or tri-methylated. Trimethylated H3K4 (H3K4me3) is preferentially detected at active genes, and is proposed to promote gene expression through recognition by transcription-activating effector molecules. Here we identify a novel class of methylated H3K4 effector domains--the PHD domains of the ING (for inhibitor of growth) family of tumour suppressor proteins. The ING PHD domains are specific and highly robust binding modules for H3K4me3 and H3K4me2. ING2, a native subunit of a repressive mSin3a-HDAC1 histone deacetylase complex, binds with high affinity to the trimethylated species. In response to DNA damage, recognition of H3K4me3 by the ING2 PHD domain stabilizes the mSin3a-HDAC1 complex at the promoters of proliferation genes. This pathway constitutes a new mechanism by which H3K4me3 functions in active gene repression. Furthermore, ING2 modulates cellular responses to genotoxic insults, and these functions are critically dependent on ING2 interaction with H3K4me3. Together, our findings establish a pivotal role for trimethylation of H3K4 in gene repression and, potentially, tumour suppressor mechanisms.
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Project description:Trimethylation of histone H3 lysine 4 (H3K4me3) is associated with transcriptional start sites and proposed to regulate transcription initiation. However, redundant functions of the H3K4 SET1/COMPASS methyltransferase complexes complicate elucidation of the specific role of H3K4me3 in transcriptional regulation. Here, we show that acute ablation of shared subunits of the SET1/COMPASS complexes leads to complete loss of all H3K4 methylation. H3K4me3 turnover occurs more rapidly than H3K4me1 and H3K4me2 and is dependent on KDM5 demethylases. Surprisingly, acute loss of H3K4me3 does not have detectable effects on transcriptional initiation but leads to a widespread decrease in transcriptional output, an increase in RNA polymerase II (RNAPII) pausing and slower elongation. Our study demonstrates a distinct role for H3K4me3 in transcriptional pause-release and elongation rather than transcriptional initiation.
2023-03-14 | PXD028858 | Pride
Project description:Histone methylation is crucial for regulating chromatin structure, gene transcription and the epigenetic state of the cell. LSD1 is a lysine-specific histone demethylase that represses transcription by demethylating histone H3 on lysine 4 (ref. 1). The LSD1 complex contains a number of proteins, all of which have been assigned roles in events upstream of LSD1-mediated demethylation apart from BHC80 (also known as PHF21A), a plant homeodomain (PHD) finger-containing protein. Here we report that, in contrast to the PHD fingers of the bromodomain PHD finger transcription factor (BPTF) and inhibitor of growth family 2 (ING2), which bind methylated H3K4 (H3K4me3), the PHD finger of BHC80 binds unmethylated H3K4 (H3K4me0), and this interaction is specifically abrogated by methylation of H3K4. The crystal structure of the PHD finger of BHC80 bound to an unmodified H3 peptide has revealed the structural basis of the recognition of H3K4me0. Knockdown of BHC80 by RNA inhibition results in the de-repression of LSD1 target genes, and this repression is restored by the reintroduction of wild-type BHC80 but not by a PHD-finger mutant that cannot bind H3. Chromatin immunoprecipitation showed that BHC80 and LSD1 depend reciprocally on one another to associate with chromatin. These findings couple the function of BHC80 to that of LSD1, and indicate that unmodified H3K4 is part of the 'histone code'. They further raise the possibility that the generation and recognition of the unmodified state on histone tails in general might be just as crucial as post-translational modifications of histone for chromatin and transcriptional regulation.
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Project description:PAT-seq approach was utilised to determine the gene expression of C. albicans. Biological duplicates of wild type and taf14∆∆ mutant samples were grown to log phase, with or without crotonate treatment (50 mM, 2 h).
2020-04-20 | GSE141229 | GEO
Project description:PAT-seq approach was utilised to determine the gene expression of C. albicans. Biological duplicates of wild type and taf14∆∆ mutant samples were grown to log phase, with or without calcofluor white treatment (20 µg/ml, 2 h).
2020-04-20 | GSE128279 | GEO