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The histone H3-lysine 4-methyltransferase Mll4 governs the development of growth hormone-releasing hormone-producing neurons

ABSTRACT: The histone H3-lysine 4-methyltransferase Mll4 governs the development of growth hormone-releasing hormone-producing neurons

PROVIDER: PRJNA628688 | ENA |

REPOSITORIES: ENA

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The histone H3-lysine 4-methyltransferase Mll4 governs the development of growth hormone-releasing hormone-producing neurons

Project description:In humans, inactivating mutations in MLL4, which encodes a histone H3-lysine 4-methyltrasferase, lead to Kabuki syndrome (KS). While dwarfism is a cardinal feature of KS, the underlying etiology remains unclear. Here we report that Mll4 is a critical regulator of the development of growth hormone-releasing hormone (GHRH)-producing neurons in the hypothalamus. The two distinct Mll4 mutant mouse models exhibited dwarfism, accompanied by impairment of developmental programs for GHRH-neurons. Our genome-wide studies revealed that, in the developing hypothalamus, Mll4 collaborates mainly with the transcription factor Nrf1 to trigger the expression of GHRH-neuronal genes. Interestingly, the deficiency of Mll4 resulted in a marked reduction of transcriptionally active histone marks in the embryonic hypothalamus, which was rescued by treatment with the histone deacetylase inhibitor AR-42. Further, AR-42 treatment restored GHRH-neuronal production in Mll4 mutant mice. Together, our results suggest that the dysregulation of MLL4-directed epigenetic control of GHRH-neuronal genes is a substantial contributing factor to dwarfism in human KS.

2020-11-07 | GSE149439 | GEO

The histone H3-lysine 4-methyltransferase Mll4 regulates the development of growth hormone-releasing hormone-producing neurons in the mouse hypothalamus.

Project description: Not available

| S-EPMC7801453 | biostudies-literature

MLL4-associated condensates counterbalance Polycomb-mediated nuclear mechanical stress in Kabuki Syndrome

Project description:The genetic elements required to tune gene expression are partitioned in active and repressive nuclear condensates. Chromatin compartments include transcriptional clusters whose dynamic establishment and functioning depends on multivalent interactions occurring among transcription factors, cofactors and basal transcriptional machinery. However how chromatin players contribute to the assembly of transcriptional condensates has not been addressed. By interrogating the effect of KMT2D haploinsufficiency in Kabuki Syndrome, we found that MLL4 contributes in the assembly of transcriptional condensates through liquid-liquid phase separation. MLL4 loss-of-function impaired Polycomb-dependent chromatin compartmentalization, altering nuclear architecture. By releasing the nuclear mechanical stress through the inhibition of the mechano-sensor ATR, we re-established the mechano-signaling of mesenchymal stem cells and their commitment towards chondrocytes both in vitro and in vivo. This study supports the notion that in Kabuki Syndrome the haploinsufficiency of MLL4 causes an altered functional partitioning of chromatin, which determines the architecture and mechanical properties of the nucleus.

2020-09-22 | PXD021616 | Pride

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.

2018-02-01 | GSE99022 | GEO

PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4 methyltransferase complex.

Project description: Not available

| S-EPMC2729684 | biostudies-literature

Selective binding of the PHD6 finger of MLL4 to histone H4K16ac links MLL4 and MOF

Project description:Histone methyltransferase MLL4 is centrally involved in transcriptional regulation and is often mutated in human diseases, including cancer and developmental disorders. MLL4 contains a catalytic SET domain that mono-methylates histone H3K4 and seven PHD fingers of unclear function. Here, we identify the PHD6 finger of MLL4 (MLL4-PHD6) as the first selective reader of the epigenetic modification H4K16ac. The solution NMR structure of MLL4-PHD6 in complex with a H4K16ac peptide along with binding and mutational analyses reveal unique mechanistic features underlying recognition of H4K16ac. Genomic studies show that one third of MLL4 chromatin binding sites overlap with H4K16ac-enriched regions in vivo and that MLL4 occupancy in a set of genomic targets depends on the acetyltransferase activity of MOF, a H4K16ac-specific acetyltransferase. The recognition of H4K16ac is conserved in the PHD7 finger of paralogous MLL3. Together, our findings highlight a novel acetyllysine reader and suggest that selective targeting of H4K16ac by MLL4 provides a direct functional link between MLL4, MOF and H4K16 acetylation.

2019-04-20 | GSE130091 | GEO

Genome-wide maps of C/EBPbeta, MLL4 and histone modifications in C/EBPbeta-overexpressed WT and MLL4-/- brown preadipocytes

Project description:Enhancers play a central role in cell-type-specific gene expression and are marked by H3K4me1/2. Active enhancers are further marked by H3K27ac. However, the methyltransferases responsible for the deposition of H3K4me1/2 on enhancers remain elusive. Furthermore, the functions of these methyltransferases on enhancers and associated cell-type-specific gene expression are poorly understood. Here, we identify MLL4 (KMT2D) as a major H3K4 mono- and di-methyltransferase in mammalian cells. Using adipogenesis and myogenesis as model systems, we show that MLL4 exhibits cell-type- and differentiation-stage-specific genomic binding and is predominantly localized on enhancers. MLL4 co-localizes with lineage-determining transcription factors (TFs) on active enhancers during differentiation. Deletion of MLL4 dramatically decreases H3K4me1/2 and H3K27ac on enhancers and leads to severe defects in cell-type-specific gene expression and cell differentiation. Finally, we provide evidence that lineage-determining TFs recruit and require MLL4 to establish enhancers critical for cell-type-specific gene expression. Together, these results identify MLL4 as an H3K4 mono-/di-methyltransferase required for enhancer activation during cell differentiation. ChIP-Seq analyses of C/EBPbeta, MLL4 and histone modifications (H3K4me1, H3K27ac) in vec- or C/EBPbeta-overexpressing, adenoviral GFP- or Cre-infected, MLL3-/-MLL4-flox/flox brown preadipocytes without induction of differentiation.

2013-12-17 | E-GEOD-50455 | biostudies-arrayexpress

Genome-wide maps of MyoD, MLL4 and histone modifications during MyoD-induced myogenesis in WT and MLL4-/- brown preadipocytes

Project description:Enhancers play a central role in cell-type-specific gene expression and are marked by H3K4me1/2. Active enhancers are further marked by H3K27ac. However, the methyltransferases responsible for the deposition of H3K4me1/2 on enhancers remain elusive. Furthermore, the functions of these methyltransferases on enhancers and associated cell-type-specific gene expression are poorly understood. Here, we identify MLL4 (KMT2D) as a major H3K4 mono- and di-methyltransferase in mammalian cells. Using adipogenesis and myogenesis as model systems, we show that MLL4 exhibits cell-type- and differentiation-stage-specific genomic binding and is predominantly localized on enhancers. MLL4 co-localizes with lineage-determining transcription factors (TFs) on active enhancers during differentiation. Deletion of MLL4 dramatically decreases H3K4me1/2 and H3K27ac on enhancers and leads to severe defects in cell-type-specific gene expression and cell differentiation. Finally, we provide evidence that lineage-determining TFs recruit and require MLL4 to establish enhancers critical for cell-type-specific gene expression. Together, these results identify MLL4 as an H3K4 mono-/di-methyltransferase required for enhancer activation during cell differentiation. ChIP-Seq of MyoD, MLL4 and histone modifications (H3K4me1, H3K4me3, and H3K27ac) in adenoviral GFP- or Cre-infected MLL3-/-;MLL4-flox/flox cells. Preadipocytes: brown preadipocytes before differentiation. D5 myocytes: 5 days after MyoD-induced myogenesis of brown preadipocytes.

2013-12-17 | E-GEOD-50465 | biostudies-arrayexpress

Regulatory Architecture of the LβT2 Gonadotrope Cell Underlying the Response to Gonadotropin-Releasing Hormone

Project description:Regulatory Architecture of the LβT2 Gonadotrope Cell Underlying the Response to Gonadotropin-Releasing Hormone

| PRJNA397847 | ENA

Placenta and uterus transcriptomes from transgenic mice expressing human corticotropin-releasing hormone in placenta

Project description:Placenta and uterus transcriptomes from transgenic mice expressing human corticotropin-releasing hormone in placenta

| PRJNA485077 | ENA