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MUC1-C ACTIVATES THE SET1A/WDR5 COMPASS COMPLEX AND H3K4 TRIMETHYLATION IN CANCER STEM CELLS

ABSTRACT: MUC1-C activates the COMPASS SET1A/WDR5 complex in integrating the induction of genes that promote chronic inflammation, pluripotency and the cancer stem cell state

ORGANISM(S): Homo sapiens

PROVIDER: GSE203055 | GEO | 2022/08/24

REPOSITORIES: GEO

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Histone H3K4 methylation-dependent and independent functions of Set1A/COMPASS in embryonic stem cell self-renewal and differentiation

Project description:Of the six members of the COMPASS (complex of proteins associated with Set1) family of histone H3 Lys4 (H3K4) methyltransferases identified in mammals, Set1A has been shown to be essential for early embryonic development and the maintenance of embryonic stem cell (ESC) self-renewal. Like its familial relatives, Set1A possesses a catalytic SET domain responsible for histone H3K4 methylation. Whether H3K4 methylation by Set1A/COMPASS is required for ESC maintenance and during differentiation has not yet been addressed. Here, we generated ESCs harboring the deletion of the SET domain of Set1A (Set1AΔSET); surprisingly, the Set1A SET domain is dispensable for ESC proliferation and self-renewal. The removal of the Set1A SET domain does not diminish bulk H3K4 methylation in ESCs; instead, only a subset of genomic loci exhibited reduction in H3K4me3 in Set1AΔSET cells, suggesting a role for Set1A independent of its catalytic domain in ESC self-renewal. However, Set1AΔSET ESCs are unable to undergo normal differentiation, indicating the importance of Set1A-dependent H3K4 methylation during differentiation. Our data also indicate that during differentiation, Set1A but not Mll2 functions as the H3K4 methylase on bivalent genes and is required for their expression, supporting a model for transcriptional switch between Mll2 and Set1A during the self-renewing-to-differentiation transition. Together, our study implicates a critical role for Set1A catalytic methyltransferase activity in regulating ESC differentiation but not self-renewal and suggests the existence of context-specific H3K4 methylation that regulates transcriptional outputs during ESC pluripotency.

2017-09-26 | GSE98988 | GEO

Nup98 recruits the Wdr82-Set1A/COMPASS complex to promoters to regulate H3K4 trimethylation in hematopoietic progenitor cells.

Project description: Not available

| S-EPMC5769767 | biostudies-literature

A Synthetic Lethality Screen Reveals ING5 as a Genetic Dependency of Catalytically Dead Set1A/COMPASS in Mouse Embryonic Stem Cells

Project description:Embryonic stem cells (ESCs) are defined by their ability to self-renew and the potential to differentiate into all tissues of the developing organism. We previously demonstrated that deleting the catalytic SET domain of the Set1A/COMPASS histone methyltransferase in mouse ESCs does not impair their viability or ability to self-renew, however, leads to defects in differentiation. The precise mechanisms by which Set1A executes these functions remain to be elucidated. In this study, we demonstrate that mice lacking the SET domain of Set1A are embryonic lethal at a stage that is unique from null alleles. To gain insight into Set1A function in regulating pluripotency, we conducted a CRISPR/Cas9-mediated dropout screen and identified the MOZ/MORF and HBO1 acetyltransferase complex member ING5 as a synthetic perturbation to Set1A. The loss of Ing5 in Set1AΔSET mESCs decreases the fitness of these cells; and the simultaneous loss of ING5 and in Set1AΔSET leads to upregulation of differentiation-associated genes. Taken together, our results point towards Set1A and ING5 as potential co-regulators of the self-renewal and differentiation status of ESCs.

2022-03-28 | GSE196946 | GEO

SET1A/COMPASS and shadow enhancers in the regulation of homeotic gene expression

Project description:The homeotic (Hox) genes are highly conserved in metazoans, where they are required for various processes in development and misregulation of their expression is associated with human cancer. In the developing embryo, Hox genes are sequentially activated in time and space according to their genomic position within Hox gene clusters. Accumulating evidence implicates both enhancer elements and non-coding RNAs in controlling this spatiotemporal expression of Hox genes, but disentangling their relative contributions is challenging. Here, we identify two cis-regulatory elements (E1 and E2) functioning as shadow enhancers to regulate the early expression of the HoxA genes. Simultaneous deletion of these shadow enhancers in embryonic stem cells leads to impaired activation of HoxA genes upon differentiation, while knockdown of a long non-coding RNA overlapping E1 has no detectable effect on their expression. Although MLL/COMPASS family of histone methyltransferases are known to activate transcription of Hox genes in other contexts, we find that individual inactivation of the MLL1-4/COMPASS family members has little effect on early Hox gene activation. Instead, we demonstrate that SET1A/COMPASS is required for full transcriptional activation of multiple Hox genes, but functions independently of the E1 and E2 cis-regulatory elements. Our results reveal multiple regulatory layers for Hox genes to fine-tune transcriptional programs essential for development.

2017-05-09 | GSE98140 | GEO

Coordinated regulation of cellular identity-associated H3K4me3 breadth by the COMPASS family

Project description:Histone H3 lysine 4 trimethylation (H3K4me3) facilitates recruitment of transcription factors and epigenetic effectors to promote transcriptional activation and ensure cellular identity. This conserved histone mark is implemented by the COMPASS (COMplex of Proteins ASsociated with Set1) family of H3K4 methyltransferases. COMPASS members Set1A and Set1B have been accredited as primary depositors of global H3K4me3 in mammalian cells. Our previous studies in mouse embryonic stem cells (ESCs) demonstrated that deleting the enzymatic SET domain of Set1A does not perturb bulk H3K4me3, indicating possible compensatory roles played by other COMPASS methyltransferases. Here, we generated a series of ESC lines harboring compounding mutations of the COMPASS enzymes. We find that Set1B is functionally redundant to Set1A in implementing H3K4me3 at highly expressed genes, while Mll2 deposits H3K4me3 at less transcriptionally active promoters. Furthermore, Set1A and Set1B are responsible for broad H3K4me3 peaks, whereas Mll2 establishes H3K4me3 with narrow breadth. Most importantly, Mll2 helps preserve global H3K4me3 levels and peak breadth. Our results illustrate the biological flexibility of such enzymes in regulating transcription in a context-dependent manner to maintain stem cell identity, which could assist our understanding of their disease liability.

2020-06-27 | GSE152595 | GEO

Structural implications of Dpy30 oligomerization for MLL/SET1 COMPASS H3K4 trimethylation.

Project description: Not available

| S-EPMC4312765 | biostudies-literature

Context Dependency of Set1/COMPASS Mediated H3 Lysine 4 Trimethylation

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

Upregulated WDR5 promotes proliferation, self-renewal and chemoresistance in bladder cancer via mediating H3K4 trimethylation.

Project description: Not available

| S-EPMC4319178 | biostudies-literature

Histone H3K4 methylation-dependent and -independent functions of Set1A/COMPASS in embryonic stem cell self-renewal and differentiation.

Project description: Not available

| S-EPMC5666672 | biostudies-literature

WDR5 regulates EMT and metastasis in breast cancer by activating TGFB pathway [ChIP-seq]

Project description:The core subunit of the COMPASS-like complex, WD Repeat Domain 5 (WDR5) has a prominent role in reprogramming and Epithelial-to-Mesenchymal transition (EMT) in different tumor types. Our evidences support a model in which WDR5 is prominent for EMT and metastasis dissemination in breast cancer patient-derived xenografts and cell lines. Moreover, WDR5 silencing abrogates TGFB pathway activation and reverts mesenchymal into epithelial phenotype, by inhibiting transcription of main master regulators of EMT (CDH2, TWIST1, SNAI1, SNAI2 and ZEB1). Our data suggest that WDR5 inhibition may be a successful approach to prevent progression of metastatic BC.

2019-12-17 | GSE113279 | GEO

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