<i>Drosophila</i>Set1 is the major histone H3 lysine 4 trimethyltransferase with role in transcription

Ardehali, M. Behfar; Mei, Amanda; Zobeck, Katie L.; Caron, Matthieu; Lis, John T.; Kusch, T

doi:10.1038/emboj.2011.194

Cited by 180 publications

(211 citation statements)

References 71 publications

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“…Nevertheless, our group and others have observed both global and local changes in H3K4me3 at promoters of genes with cancer-promoting activity, in cancer cells (14,25,26,53,54). Methylation of H3K4 is primarily catalyzed by TrxG members, with the modification of H3K4me3 chiefly catalyzed by hSETD1A (26,27,(55)(56)(57)(58). Here, we showed increase in both global H3K4me3 and hSETD1A protein levels in cultured breast cancer cell lines (Fig.…”

Section: Discussionmentioning

confidence: 64%

Histone Methyltransferase hSETD1A Is a Novel Regulator of Metastasis in Breast Cancer

Salz

Deng

Pampo

et al. 2015

Molecular Cancer Research

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Epigenetic alteration is a hallmark of all cancers. Such alterations lead to modulation of fundamental cancer-related functions, such as proliferation, migration, and invasion. In particular, methylation of Histone H3 Lysine 4 (H3K4), a histone mark generally associated with transcriptional activation, is altered during progression of several human cancers. While the depletion of H3K4 demethylases promotes breast cancer metastasis, the effect of H3K4 methyltransferases on metastasis is not clear. Nevertheless, gene duplications in the human SETD1A (hSETD1A) H3K4 methyltransferase are present in almost half of breast cancers. Herein, expression analysis determined that hSETD1A is upregulated in multiple metastatic human breast cancer cell lines and clinical tumor specimens. Ablation of hSETD1A in breast cancer cells led to a decrease in migration and invasion in vitro and to a decrease in metastasis in nude mice. Furthermore, a group of matrix metalloproteinases (including MMP2, MMP9, MMP12, MMP13, and MMP17) were identified which were downregulated upon depletion of hSETD1A and demonstrated a decrease in H3K4me3 at their proximal promoters based on chromatin immunoprecipitation analysis. These results provide evidence for a functional and mechanistic link among hSETD1A, MMPs, and metastasis in breast cancer, thereby supporting an oncogenic role for hSETD1A in cancer.Implications: This study reveals that hSETD1A controls tumor metastasis by activating MMP expression and provides an epigenetic link among hSETD1A, MMPs, and metastasis of breast cancer.

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Section: Discussionmentioning

confidence: 64%

Histone Methyltransferase hSETD1A Is a Novel Regulator of Metastasis in Breast Cancer

Salz

Deng

Pampo

et al. 2015

Molecular Cancer Research

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“…While we were preparing this report, Ardehali et al (2011) reported that dSet1 is associated within a COM-PASS complex and is responsible for the majority of H3K4 methylation in Drosophila S2 tissue culture cells. Mohan et al (2011) have also recently reported on the central role of dSet1; moreover, they have comprehensively characterized all three COMPASS complexes in Drosophila containing dSet1, Trx, or Trr and associated proteins (Mohan et al 2011).…”

Section: Discussionmentioning

confidence: 99%

dSet1 Is the Main H3K4 Di- and Tri-Methyltransferase ThroughoutDrosophilaDevelopment

Hallson

Hollebakken²,

Li³

et al. 2012

Genetics

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In eukaryotes, the post-translational addition of methyl groups to histone H3 lysine 4 (H3K4) plays key roles in maintenance and establishment of appropriate gene expression patterns and chromatin states. We report here that an essential locus within chromosome 3L centric heterochromatin encodes the previously uncharacterized Drosophila melanogaster ortholog (dSet1, CG40351) of the Set1 H3K4 histone methyltransferase (HMT). Our results suggest that dSet1 acts as a "global" or general H3K4 diand trimethyl HMT in Drosophila. Levels of H3K4 di-and trimethylation are significantly reduced in dSet1 mutants during late larval and post-larval stages, but not in animals carrying mutations in genes encoding other well-characterized H3K4 HMTs such as trr, trx, and ash1. The latter results suggest that Trr, Trx, and Ash1 may play more specific roles in regulating key cellular targets and pathways and/ or act as global H3K4 HMTs earlier in development. In yeast and mammalian cells, the HMT activity of Set1 proteins is mediated through an evolutionarily conserved protein complex known as Complex of Proteins Associated with Set1 (COMPASS). We present biochemical evidence that dSet1 interacts with members of a putative Drosophila COMPASS complex and genetic evidence that these members are functionally required for H3K4 methylation. Taken together, our results suggest that dSet1 is responsible for the bulk of H3K4 di-and trimethylation throughout Drosophila development, thus providing a model system for better understanding the requirements for and functions of these modifications in metazoans.

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“…Recent studies have attributed H3K4me1 to TRR (Ardehali et al 2011;Herz et al 2012), although it has also been assigned to Trithorax (Tie et al 2014). Significantly, CBP and TRR each form a complex containing UTX (Mohan et al 2011;Tie et al 2012), suggesting that these complexes may work in tandem demethylating H3K27 and writing H3K27ac and H3K4me1.…”

Section: Global Increase Of H3k27ac and H3k4me1mentioning

confidence: 99%

Genome-wide activities of Polycomb complexes control pervasive transcription

et al. 2015

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Polycomb group (PcG) complexes PRC1 and PRC2 are well known for silencing specific developmental genes. PRC2 is a methyltransferase targeting histone H3K27 and producing H3K27me3, essential for stable silencing. Less well known but quantitatively much more important is the genome-wide role of PRC2 that dimethylates ∼70% of total H3K27. We show that H3K27me2 occurs in inverse proportion to transcriptional activity in most non-PcG target genes and intergenic regions and is governed by opposing roaming activities of PRC2 and complexes containing the H3K27 demethylase UTX. Surprisingly, loss of H3K27me2 results in global transcriptional derepression proportionally greatest in silent or weakly transcribed intergenic and genic regions and accompanied by an increase of H3K27ac and H3K4me1. H3K27me2 therefore sets a threshold that prevents random, unscheduled transcription all over the genome and even limits the activity of highly transcribed genes. PRC1-type complexes also have global roles. Unexpectedly, we find a pervasive distribution of histone H2A ubiquitylated at lysine 118 (H2AK118ub) outside of canonical PcG target regions, dependent on the RING/Sce subunit of PRC1-type complexes. We show, however, that H2AK118ub does not mediate the global PRC2 activity or the global repression and is predominantly produced by a new complex involving L(3)73Ah, a homolog of mammalian PCGF3.

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DrosophilaSet1 is the major histone H3 lysine 4 trimethyltransferase with role in transcription

Cited by 180 publications

References 71 publications

Histone Methyltransferase hSETD1A Is a Novel Regulator of Metastasis in Breast Cancer

Histone Methyltransferase hSETD1A Is a Novel Regulator of Metastasis in Breast Cancer

dSet1 Is the Main H3K4 Di- and Tri-Methyltransferase ThroughoutDrosophilaDevelopment

Genome-wide activities of Polycomb complexes control pervasive transcription

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