Interplay of BAF and MLL4 promotes enhancer activation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA634764 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11837700.fastq.gz | Fastqsanger.gz | |||
| SRR11837701.fastq.gz | Fastqsanger.gz | |||
| SRR11837702.fastq.gz | Fastqsanger.gz | |||
| SRR11837703.fastq.gz | Fastqsanger.gz | |||
| SRR11837704.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 98 |
Similar Datasets
Project description:Cell type-specific enhancers are activated by coordinated actions of lineage-determining transcription factors (LDTFs) and chromatin regulators. The SWI/SNF complex BAF and the histone H3K4 methyltransferase MLL4 (KMT2D) are both implicated in enhancer activation. However, the interplay between BAF and MLL4 in enhancer activation remains unclear. Using adipogenesis as a model system, we identify BAF as the major SWI/SNF complex that colocalizes with LDTFs and MLL4 on active enhancers during cell differentiation. Similar to MLL4, BAF is required for cell type-specific gene induction in adipogenesis. In contrast, another SWI/SNF complex PBAF is enriched on promoters and is dispensable for adipogenesis. By depleting BAF subunits SMARCA4 (BRG1) and SMARCB1 (SNF5) as well as MLL4 in cells, we show that BAF and MLL4 reciprocally regulate each other’s binding on active enhancers before and during adipogenesis. By focusing on enhancer activation by the adipogenic transcription factor C/EBPβ without inducing cell differentiation, we provide direct evidence to support an interdependent relationship between BAF and MLL4 in activating cell type-specific enhancers. Together, these findings suggest that the interplay of BAF and MLL4 promotes LDTF-dependent activation of cell type-specific enhancers.
2021-01-07 | GSE151115 | GEO
Project description:Cell type-specific enhancers are activated by coordinated actions of lineage-determining transcription factors (LDTFs) and chromatin regulators. The SWI/SNF chromatin remodeling complex BAF and the histone H3K4 methyltransferase MLL4 (KMT2D) are both implicated in enhancer activation. However, the interplay between BAF and MLL4 in enhancer activation remains unclear. Using adipogenesis as a model system, we identify BAF as the major SWI/SNF complex that colocalizes with MLL4 and LDTFs on active enhancers and is required for cell differentiation. In contrast, the promoter enriched SWI/SNF complex PBAF is dispensable for adipogenesis. By depleting BAF subunits SMARCA4 (BRG1) and SMARCB1 (SNF5) as well as MLL4 in cells, we show that BAF and MLL4 reciprocally regulate each other's binding on active enhancers before and during adipogenesis. By focusing on enhancer activation by the adipogenic pioneer transcription factor C/EBPβ without inducing cell differentiation, we provide direct evidence for an interdependent relationship between BAF and MLL4 in activating cell type-specific enhancers. Together, these findings reveal a positive feedback between BAF and MLL4 in promoting LDTF-dependent activation of cell type-specific enhancers.
| S-EPMC7955098 | biostudies-literature
Project description:MLL4 is an essential subunit of the H3K4 methylation complexes. We report that Mll4 deficiency compromised Treg development and resulted in substantial decreases in H3K4me1 and chromatin interaction at putative enhancers, a remarkable portion of which were not direct targets of MLL4 but were interacting with Mll4-bound sites. The decrease in H3K4me1 and chromatin interaction at the MLL4-unbound enhancers correlated with MLL4 binding at distant interacting regions. Deletion of an upstream MLL4 binding site reduced H3K4me1 at the FoxP3 regulatory elements looped to the MLL4 binding site and compromised both tTreg and iTreg differentiation. We show that MLL4 catalyses H3K4 methylation at distant unbound enhancers via chromatin looping, thus providing a new mechanism of regulating T cell enhancer landscape and impacting Treg differentiation.
2017-07-18 | GSE69162 | GEO
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:Histone H3K4me1/2 methyltransferases MLL3/MLL4 and H3K27 acetyltransferases CBP/p300 are major enhancer epigenomic writers. To understand how these epigenomic writers orchestrate enhancer landscapes during cell differentiation, we have profiled genomic binding of MLL4, CBP, lineage-determining transcription factors, as well as transcriptome and epigenome during adipogenesis of immortalized preadipocytes derived from mouse brown adipose tissue (BAT). We show that MLL4 and CBP drive the dynamic enhancer epigenome, which correlates with the dynamic transcriptome. MLL3/MLL4 are required for CBP/p300 binding on enhancers activated during adipogenesis. Further, we show that MLL4 and CBP identify super-enhancers of adipogenesis and that MLL3/MLL4 are required for the formation of super-enhancers. Finally, in brown adipocytes differentiated in culture, MLL4 identifies primed super-enhancers of genes fully activated in BAT such as the thermogenic Ucp1. Comparison of MLL4-defined super-enhancers in brown and white adipogenesis predicted a list of brown-specific super-enhancers SEs associated genes that are likely to be important to BAT functions. These results establish MLL3/MLL4 and CBP/p300 as master enhancer epigenomic writers and suggest that enhancer-priming by MLL3/MLL4 followed by enhancer-activation by CBP/p300 sequentially shape dynamic enhancer landscapes during cell differentiation. Our data also provide a rich resource for understanding epigenomic regulation of brown adipogenesis.
2017-01-01 | GSE74189 | GEO
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
Project description:H3.3K4M targets MLL3/MLL4 to prevent enhancer activation in adipogenesis
| PRJNA435436 | ENA
Project description:Enhancer activation is a critical step for gene activation. Here we report a novel epigenetic crosstalk at enhancers between the UTX (H3K27 demethylase)-MLL4 (H3K4 methyltransferase) complex and the histone acetyltransferase p300. We demonstrate that UTX, in a demethylase activity-independent manner, facilitates conversion of naïve (unmarked) enhancers in embryonic stem cells to an active (H3K4me1+/H3K27ac+) state by recruiting and coupling the enzymatic functions of MLL4 and p300. Loss of UTX leads to attenuated enhancer activity, characterized by reduced levels of H3K4me1 and H3K27ac as well as impaired transcription. The UTX-MLL4 complex enhances p300-dependent H3K27 acetylation through UTX-dependent stimulation of p300 recruitment while MLL4-mediated H3K4 monomethylation, reciprocally, requires p300 function. Importantly, MLL4-generated H3K4me1 further enhances p300-dependent transcription. This work reveals a previously unrecognized cooperativity among enhancer-associated chromatin modulators, including a unique function for UTX, in establishing an “active enhancer landscape” and defines a mechanism for the joint deposition of H3K4me1 and H3K27ac.
2017-07-06 | GSE97702 | GEO
Project description:Enhancer activation is a critical step for gene activation. Here we report a novel epigenetic crosstalk at enhancers between the UTX (H3K27 demethylase)-MLL4 (H3K4 methyltransferase) complex and the histone acetyltransferase p300. We demonstrate that UTX, in a demethylase activity-independent manner, facilitates conversion of naïve (unmarked) enhancers in embryonic stem cells to an active (H3K4me1+/H3K27ac+) state by recruiting and coupling the enzymatic functions of MLL4 and p300. Loss of UTX leads to attenuated enhancer activity, characterized by reduced levels of H3K4me1 and H3K27ac as well as impaired transcription. The UTX-MLL4 complex enhances p300-dependent H3K27 acetylation through UTX-dependent stimulation of p300 recruitment while MLL4-mediated H3K4 monomethylation, reciprocally, requires p300 function. Importantly, MLL4-generated H3K4me1 further enhances p300-dependent transcription. This work reveals a previously unrecognized cooperativity among enhancer-associated chromatin modulators, including a unique function for UTX, in establishing an “active enhancer landscape” and defines a mechanism for the joint deposition of H3K4me1 and H3K27ac.
2017-07-06 | GSE97701 | GEO
Project description:Enhancers play a key role in regulating cell type-specific gene expression and are marked by histone modifications such as methylation and acetylation. Mono-methylation of lysine 4 on histone H3 (H3K4me1) initially primes enhancers, preceding enhancer activation via acetylation of lysine 27 on histone H3 (H3K27ac). MLL4 is a major enhancer H3K4 mono-methyltransferase with partial functional redundancy with MLL3. However, how H3K4me1 affects enhancer regulation in cell differentiation has remained unclear. By screening several lysine-to-methionine mutants of H3.3, we first found that depletion of H3K4 methylation by H3.3K4M mutation severely impairs adipogenesis in culture. Using tissue-specific expression of H3.3K4M in mice, we further demonstrate that H3.3K4M inhibits adipose tissue and muscle development in vivo. Mechanistically, H3.3K4M destabilizes MLL3/4 proteins but not other members of the mammalian Set1-like H3K4 methyltransferase family and prevents MLL3/4-mediated enhancer activation in adipogenesis. Using tissue-specific deletion of the enzymatic SET domain of MLL3/4 in mice, we also show that deletion of the SET domain prevents adipose tissue and muscle development in vivo and inhibits adipogenesis by destabilizing MLL3/4 in vitro. Notably, H3.3K4M expression mimics MLL3/4 SET domain deletion in preventing adipogenesis. Interestingly, H3.3K4M does not affect adipose tissue maintenance and function, suggesting that MLL3/4-mediated H3K4 methylation is dispensable for the maintenance and function of differentiated adipocytes. Together, our findings suggest that H3.3K4M targets MLL3/4 to prevent enhancer activation in adipogenesis.
2018-10-25 | GSE110972 | GEO