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Histone H3K4 monomethylation catalyzed by Trr and mammalian COMPASS-like proteins at enhancers is dispensable for development and viability

ABSTRACT: Histone H3 lysine 4 monomethylation (H3K4me1) is an evolutionarily conserved feature of enhancer chromatin catalyzed by the COMPASS-like methyltransferase family that includes Trr in Drosophila melanogaster and MLL3 (encoded by KMT2C) and MLL4 (encoded by KMT2D) in mammals. Here we demonstrate that Drosophila embryos expressing catalytically deficient Trr eclose and develop to productive adulthood. Parallel experiments with a trr allele that augments enzyme product specificity show that conversion of H3K4me1 at enhancers to H3K4me2 and H3K4me3 is also compatible with life and results in minimal changes in gene expression. Similarly, loss of the catalytic SET domains of MLL3 and MLL4 in mouse embryonic stem cells (mESCs) does not disrupt selfrenewal. Drosophila embryos with trr alleles encoding catalytic mutants manifest subtle developmental abnormalities when subjected to temperature stress or altered cohesin levels. Collectively, our findings suggest that animal development can occur in the context of Trr or mammalian COMPASS-like proteins deficient in H3K4 monomethylation activity and point to a possible role for H3K4me1 on cis-regulatory elements in specific settings to fine-tune transcriptional regulation in response to environmental stress.

ORGANISM(S): Mus musculus Drosophila melanogaster

PROVIDER: GSE95781 | GEO | 2017/10/02

SECONDARY ACCESSION(S): PRJNA378409

REPOSITORIES: GEO

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The MLL3/MLL4 branch of the COMPASS family regulates H3K4 monomethylation at enhancers

Project description:Histone H3 lysine 4 (H3K4) can be mono-, di-, and trimethylated by members of the COMPASS (COMplex of Proteins ASsociated with Set1) family from yeast to human and these modifications can be found at distinct regions of the genome. Monomethylation of histone H3K4 (H3K4me1) is relatively more enriched at metazoan enhancer regions compared to trimethylated histone H3K4 (H3K4me3), which are found at transcription start sites in all eukaryotes. Our recent studies in Drosophila demonstrated that the Trithorax-related (Trr) branch of the COMPASS family regulates enhancer activity and is responsible for the implementation of H3K4me1 at these regions. There are six COMPASS family members in mammals, two of which, MLL3 and MLL4, are most closely related to Drosophila Trr. Here, we use ChIP-seq of this class of COMPASS family members in both human HCT116 cells and mouse embryonic stem cells and find that MLL4 is preferentially found at enhancer regions. MLL3 and MLL4 are frequently mutated in cancer, and indeed, the widely used HCT116 cancer cell line contains inactivating mutations in the MLL3 gene. Using HCT116 cells in which MLL4 has also been knocked out, we demonstrate that MLL4 is a major regulator of H3K4me1 in these cells, with the greatest loss of monomethylation at enhancer regions. Moreover, we found a redundant role between Mll3 and Mll4 in enhancer H3K4 monomethylation in mouse embryonic fibroblast (MEF) cells. These findings suggest that mammalian MLL3/MLL4 function in the regulation of enhancer activity and enhancer-promoter communication during gene expression and that mutations of MLL3 and MLL4 found in cancer could exert their properties through enhancer malfunction. ChIP-Seq in mouse embryonic stem (mES) cells for MLL4. ChIP-seq of MLL4 and p300 in human parental HCT116 cells. ChIP-seq of H3K4me1, H3K4me2 and H3K4me3 in parental HCT116 cells and HCT116 cells with Mll4∆set.

2013-09-30 | E-GEOD-51176 | biostudies-arrayexpress

A small UTX stabilization domain of Trr is conserved within mammalian MLL3-4/COMPASS and is sufficient to rescue loss of viability in null animals

Project description:Catalytic-inactivating mutations within the Drosophila enhancer H3K4 monomethyltransferase Trr and its mammalian homologs, MLL3/4, cause only minor changes in gene expression compared to whole-gene deletions for these COMPASS members. To identify essential histone methylatransferase-independent functions of Trr, we screened to identify a minimal Trr domain sufficient to rescue Trr-null lethality and demonstrate that this domain binds and stabilizes Utx in vivo. Using the homologous MLL3/MLL4 human sequences, we mapped a short ~80 amino acid UTX-Stabilization-Domain (USD) that promotes UTX stability in the absence of the rest of MLL3/4. Nuclear UTX stability is enhanced when the USD is fused with the MLL4 HMG-box. Thus, COMPASS-dependent UTX stabilization is an essential non-catalytic function of Trr/MLL3/MLL4, suggesting that stabilizing UTX could be a therapeutic strategy for cancers with MLL3/4 loss-of-function mutations.

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The MLL3/MLL4 branch of the COMPASS family regulates H3K4 monomethylation at enhancers

2013-09-30 | GSE51176 | GEO

Enhancer-associated H3K4 mono-methylation by Drosophila Trithorax-related, the Drosophila homolog of Mll3/Mll4

Project description:Mono-methylation of histone H3 on lysine 4 (H3K4me1) and acetylation of histone H3 on lysine 27 (H3K27ac) are histone modifications that are highly enriched over the body of actively transcribed genes and enhancers. Although in yeast all H3K4 methylation patterns including H3K4me1 are implemented by Set1/COMPASS, there are three classes of COMPASS-like complexes in Drosophila that could carry out H3K4me1 on enhancers: dSet1, Trithorax and Trithorax-related (Trr). Here, we report that Trr, the Drosophila homolog of mammalian Mll3/4, can function as a major H3K4 mono-methyltransferase on enhancers in vivo. Loss of Trr results in a global decrease of H3K4me1 and H3K27ac in various tissues. Assays with the cut wing margin enhancer imply a functional role for Trr in enhancer-mediated processes. A genome-wide analysis demonstrates that Trr is required for H3K4me1 and H3K27ac on chromatin signatures that resemble the histone modification patterns described for enhancers. Since Trr and mammalian Mll3/4 complexes are distinguished by bearing a unique subunit, the H3K27 demethylase UTX, we propose a model in which the H3K4 mono-methyltransferase Trr, and the H3K27 demethylase, UTX, cooperate to regulate the transition from inactive/poised to active enhancers. ChIP-seq of Trr, LPT, UTX in Drosophila S2 Cells. ChIP-seq of H3K4me1, H3K4me3, H3K27ac, H3K27me3 in WT and Trr knock-down Drosophila S2 cells. ChIP-seq of H3K4me1, H3K27me3 in LPT knock-down Drosophila S2 cells. ChIP-seq of LPT and UTX in Trr knock-down Drosophila S2 cells. ChIP-seq of H3K4me1 and H3K27me3 in MLL1(+/+), MLL1(-/-), MLL3(+/+), and MLL3(-/-) Mouse Embryonic Fibroblasts (MEFs).

2012-12-01 | E-GEOD-41440 | biostudies-arrayexpress

Enhancer-associated H3K4 mono-methylation by Drosophila Trithorax-related, the Drosophila homolog of Mll3/Mll4

2012-12-01 | GSE41440 | GEO

Distinct roles for COMPASS core subunits Set1, Trx, and Trr in the epigenetic regulation of Drosophila heart development

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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Mll3 and Mll4 facilitate enhancer RNA synthesis and transcriptional elongation from promoters independently of H3K4 monomethylation

Project description:Monomethylation of histone H3 at lysine 4 (H3K4me1) and acetylation of histone H3 at lysine 27 (H3K27ac) are correlated with transcriptionally engaged enhancer elements, but the functional impact of these modifications on enhancer activity is not well understood. Here we used CRISPR/Cas9 genome editing to separate catalytic activity-dependent and independent functions of Mll3 (Kmt2c) and Mll4 (Kmt2d, Mll2), the major enhancer H3K4 monomethyltransferases. Loss of Mll3/4 catalytic activity and H3K4me1 from enhancers causes partial depletion of H3K27ac, but surprisingly minor effects on enhancer Pol II binding, enhancer RNA (eRNA) transcription and gene expression. In contrast, loss of Mll3/4 proteins results in dramatic reduction of eRNA production, concomitant with impaired transcriptional elongation at adjacent promoters. Altogether our results suggest the major coactivator function of Mll3/4 is largely independent of H3K4me1 and instead linked to enhancer Pol II occupancy, eRNA transcription and long-range influence on elongation at target promoters.

2017-05-05 | GSE98063 | GEO

An Mll4/COMPASS-Lsd1 epigenetic axis governs enhancer function and pluripotency transition in embryonic stem cells

Project description:Chromatin regulators control cellular differentiation by orchestrating dynamic developmental gene expression programs, and hence, malfunctions in the regulation of chromatin state contribute to both developmental disorders and disease state. Mll4 (Kmt2d), a member of the COMPASS (COMplex of Proteins ASsociated with Set1) protein family that implements histone H3 lysine 4 monomethylation (H3K4me1) at enhancers, is essential for embryonic development and functions as a pancancer tumor suppressor. We define the roles of Mll4/COMPASS and its catalytic activity in the maintenance and exit of ground-state pluripotency in murine embryonic stem cells (ESCs). Mll4 is required for ESC to exit the naive pluripotent state; however, its intrinsic catalytic activity is dispensable for this process. The depletion of the H3K4 demethylase Lsd1 (Kdm1a) restores the ability of Mll4 null ESCs to transition from naive to primed pluripotency. Thus, we define an opposing regulatory axis, wherein Lsd1 and associated co-repressors directly repress Mll4-activated gene targets. This finding has broad reaching implications for human developmental syndromes and the treatment of tumors carrying Mll4 mutations.

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2019-01-23 | GSE118314 | GEO

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