MLL4 establishes enhancer-associated condensates to counterbalance Polycomb-mediated nuclear mechanical stress in Kabuki Syndrome [3'UTR RNA-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA559272 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9925440.fastq.gz | Fastqsanger.gz | |||
| SRR9925441.fastq.gz | Fastqsanger.gz | |||
| SRR9925442.fastq.gz | Fastqsanger.gz | |||
| SRR9925443.fastq.gz | Fastqsanger.gz | |||
| SRR9925444.fastq.gz | Fastqsanger.gz |
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Project description:The genetic elements required to tune gene expression are partitioned in active and repressive nuclear condensates. These chromatin compartments include enhancer-associated clusters whose dynamic establishment and functioning depends on multivalent interactions occurring among transcription factors, cofactors and basal transcriptional machinery. However how chromatin modifiers contribute to the assembly of enhancer-associated condensates have not been addressed. We herein defined the non-catalytic function of MLL4 in driving the formation active nuclear condensates and its interplay with Polycomb compartment in determining the nuclear architecture. By interrogating the role of haploinsufficiency of KMT2D in Kabuki Syndrome, we found that MLL4 guides the assembly of enhancer-associated condensates through liquid-liquid phase separation. The loss-of-function of MLL4 impaired the correct chromatin compartmentalization of Polycomb proteins, altering nuclear architecture. By releasing the nuclear mechanical stress through the inhibition of the mechano-sensor ATR, we re-established the mechano-signaling of MSCs and their commitments towards chondrocytes. This study supports the notion that MLL4 contributes to the functional partitioning of chromatin, which is required to determine the structure and the mechanical properties of the nucleus.
2020-09-09 | GSE135550 | GEO
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
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 depend on multivalent interactions occurring among transcription factors, cofactors and basal transcriptional machinery. However, how chromatin players contribute to the assembly of transcriptional condensates is poorly understood. By interrogating the effect of KMT2D (also known as MLL4) haploinsufficiency in Kabuki syndrome, we found that mixed lineage leukemia 4 (MLL4) contributes to the assembly of transcriptional condensates through liquid-liquid phase separation. MLL4 loss of function impaired Polycomb-dependent chromatin compartmentalization, altering the nuclear architecture. By releasing the nuclear mechanical stress through inhibition of the mechanosensor ATR, we re-established the mechanosignaling 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.
| S-EPMC7610431 | biostudies-literature
Project description:Clusters of enhancers called super-enhancers are associated with gene activation. Broad trimethyl histone H3 lysine 4 (H3K4me3) often defines actively transcribed tumor suppressor genes. However, how these epigenetic signatures are regulated for tumor suppression is poorly understood. Here, we show that brain-specific knockout of the H3K4 methyltransferase MLL4 (aka KMT2D) in mice spontaneously induces cerebellar tumors in brain while indirectly increasing expression of oncogenic programs, such as Ras activators and Notch pathway components. Mll4 loss caused widespread impairment of super-enhancers and broad H3K4me3. Notably, Mll4 loss reduced super-enhancer and broad H3K4me3 signals in tumor suppressor genes co-marked by both signatures, including Dnmt3a and Bcl6. MLL4 upregulates DNMT3A-mediated DNA methylation to downregulate expression of Ras activators and increases Bcl6 expression to suppress the Notch pathway. These findings suggest an unanticipated epigenetic tumor-suppressive mechanism in which MLL4 is required for establishing super-enhancers and broad H3K4me3 for anti-tumor programs in normal cells.
2018-11-13 | GSE95626 | GEO
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
Project description:Cancer genome sequencing consortiums have recently catalogued an abundance of somatic mutations in the chromatin-modifying enzymes that regulate enhancer chromatin function across a wide range of human cancers. Defining the molecular mechanisms underlying the potential oncogenic function for these epigenetic mutations could serve as the basis for precision medicine approaches for cancer treatment. MLL4 (KMT2D) is a key histone lysine mono-methyltransferase within the COMplex of Proteins ASsociated with Set1 (COMPASS) family that regulates chromatin at enhancers, potentially functions as a tumor suppressor and is highly mutated in a large number of human cancers. We report that the mutations which cause MLL4 protein truncation also alter its subcellular localization, resulting in loss-of-function in the nucleus and gain-of-function in the cytoplasm. We demonstrate that isogenic correction of MLL4 truncation mutation rescues the aberrant localization phenotype and restores multiple MLL4 regulatory functions, including COMPASS integrity and stabilization, histone H3K4 mono-methylation, enhancer activation, and gene regulation. Moreover, isogenic correction diminishes the sensitivity of MLL4-mutated cancer cells to targeted metabolic inhibition. Using immunohistochemistry (IHC), we identified cytoplasmic MLL4 unique to the tissue of bladder cancer patients with MLL4 mutations. Using a preclinical carcinogen bladder cancer mouse model, we demonstrate that truncated, cytoplasmic MLL4 can be a biomarker for MLL4-mutated bladder cancers and predicts response to targeted metabolic inhibition therapy. We propose using the cytoplasmic MLL4 truncation phenotype as a prognostic marker in bladder cancer. We also highlight the broader potential for patient stratification based on MLL4 mutation status in MLL4 truncation diseases, including human cancers and Kabuki Syndrome.
2023-12-05 | GSE246058 | GEO
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
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
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
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 MLL4 binding profiles at D0 (day 0), D2 (day 2), and D7 (day 7) of adipogenesis in WT (MLL3-/-) and MLL4 KO (MLL3-/-;MLL4-/-) brown preadipocytes. D0 and D2 input DNA samples can be found in GSE50417.
2013-12-17 | E-GEOD-50209 | biostudies-arrayexpress