Coordinated regulation of cellular identity-associated H3K4me3 breadth by the COMPASS family
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA639810 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12024700.fastq.gz | Fastqsanger.gz | |||
| SRR12024800.fastq.gz | Fastqsanger.gz | |||
| SRR12024900.fastq.gz | Fastqsanger.gz | |||
| SRR12024701.fastq.gz | Fastqsanger.gz | |||
| SRR12024801.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 264 |
Similar Datasets
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
Project description:Set1A and Set1B, two members of the COMPASS family of methyltransferases that methylate the histone H3 lysine 4 (H3K4) residue, have been accredited as primary depositors of global H3K4 trimethylation (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 COMPASS methyltransferases. 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. While Set1A-B/COMPASS is responsible for broad H3K4me3 peaks, Mll2/COMPASS establishes H3K4me3 with narrow breadth. Additionally, Mll2 helps preserve global H3K4me3 levels and peak breadth in the absence of Set1A-B activity. Our results illustrate the biological flexibility of such enzymes in regulating transcription in a context-dependent manner to maintain stem cell identity.
| S-EPMC7314515 | biostudies-literature
Project description:Histone H3 lysine 4 tri-methylation (H3K4me3) is abundant in MLL-rearranged (MLL-r) acute myeloid leukemia (AML) cells, but the enzymes responsible and their roles remain unclear. In this study, we perform a CRISPR-tiling screen against known H3K4 methylation modifiers in MLL-r AML model. We found the non-redundant roles of H3K4 methyltransferase SETD1B for growth regulation in NrasG12D or FLT3-ITD-expressing AML cells that exhibit cytokine-independent growth. The disruption of SETD1B catalytic SET domain causes cell cycle arrest, apoptosis, cell differentiation and a downregulation of gene expression, especially in the MYC pathway. H3K4me3 and SETD1B are distributed to the gene body of Myc, and the loss of SETD1B SET domain result in a significant decrease in H3K4me3 breadth. Overexpression of MYC significantly restores the growth defect and transcriptional perturbation in SETD1B SET domain mutant cells. In the meantime, the expression of MYC does not rescue the reduced H3K4me3 breadth and RNA polymerase II elongation in SETD1B mutant cells. A disruption of H3K4 demethylase KDM5C enhances global H3K4me3 level and promotes the proliferation of AML cell, and partially rescues the defective cell growth of SETD1B SET domain mutant cells. These data indicate that SETD1B is required for both H3K4me3 breadth and Myc expression to support advanced AML cell proliferation. Thus, a thorough understanding of the SETD1B-mediated H3K4me3 breadth will be critical for the development of markers and therapies for leukemia subtypes that are MYC-dependent.
2025-04-28 | GSE248322 | GEO
Project description:Histone H3 lysine 4 tri-methylation (H3K4me3) is abundant in MLL-rearranged (MLL-r) acute myeloid leukemia (AML) cells, but the enzymes responsible and their roles remain unclear. In this study, we perform a CRISPR-tiling screen against known H3K4 methylation modifiers in MLL-r AML model. We found the non-redundant roles of H3K4 methyltransferase SETD1B for growth regulation in NrasG12D or FLT3-ITD-expressing AML cells that exhibit cytokine-independent growth. The disruption of SETD1B catalytic SET domain causes cell cycle arrest, apoptosis, cell differentiation and a downregulation of gene expression, especially in the MYC pathway. H3K4me3 and SETD1B are distributed to the gene body of Myc, and the loss of SETD1B SET domain result in a significant decrease in H3K4me3 breadth. Overexpression of MYC significantly restores the growth defect and transcriptional perturbation in SETD1B SET domain mutant cells. In the meantime, the expression of MYC does not rescue the reduced H3K4me3 breadth and RNA polymerase II elongation in SETD1B mutant cells. A disruption of H3K4 demethylase KDM5C enhances global H3K4me3 level and promotes the proliferation of AML cell, and partially rescues the defective cell growth of SETD1B SET domain mutant cells. These data indicate that SETD1B is required for both H3K4me3 breadth and Myc expression to support advanced AML cell proliferation. Thus, a thorough understanding of the SETD1B-mediated H3K4me3 breadth will be critical for the development of markers and therapies for leukemia subtypes that are MYC-dependent.
2025-04-28 | GSE248318 | GEO
Project description:Histone H3 lysine 4 tri-methylation (H3K4me3) is abundant in MLL-rearranged (MLL-r) acute myeloid leukemia (AML) cells, but the enzymes responsible and their roles remain unclear. In this study, we perform a CRISPR-tiling screen against known H3K4 methylation modifiers in MLL-r AML model. We found the non-redundant roles of H3K4 methyltransferase SETD1B for growth regulation in NrasG12D or FLT3-ITD-expressing AML cells that exhibit cytokine-independent growth. The disruption of SETD1B catalytic SET domain causes cell cycle arrest, apoptosis, cell differentiation and a downregulation of gene expression, especially in the MYC pathway. H3K4me3 and SETD1B are distributed to the gene body of Myc, and the loss of SETD1B SET domain result in a significant decrease in H3K4me3 breadth. Overexpression of MYC significantly restores the growth defect and transcriptional perturbation in SETD1B SET domain mutant cells. In the meantime, the expression of MYC does not rescue the reduced H3K4me3 breadth and RNA polymerase II elongation in SETD1B mutant cells. A disruption of H3K4 demethylase KDM5C enhances global H3K4me3 level and promotes the proliferation of AML cell, and partially rescues the defective cell growth of SETD1B SET domain mutant cells. These data indicate that SETD1B is required for both H3K4me3 breadth and Myc expression to support advanced AML cell proliferation. Thus, a thorough understanding of the SETD1B-mediated H3K4me3 breadth will be critical for the development of markers and therapies for leukemia subtypes that are MYC-dependent.
2025-04-28 | GSE248325 | GEO
Project description:Histone H3 lysine 4 tri-methylation (H3K4me3) is abundant in MLL-rearranged (MLL-r) acute myeloid leukemia (AML) cells, but the enzymes responsible and their roles remain unclear. In this study, we perform a CRISPR-tiling screen against known H3K4 methylation modifiers in MLL-r AML model. We found the non-redundant roles of H3K4 methyltransferase SETD1B for growth regulation in NrasG12D or FLT3-ITD-expressing AML cells that exhibit cytokine-independent growth. The disruption of SETD1B catalytic SET domain causes cell cycle arrest, apoptosis, cell differentiation and a downregulation of gene expression, especially in the MYC pathway. H3K4me3 and SETD1B are distributed to the gene body of Myc, and the loss of SETD1B SET domain result in a significant decrease in H3K4me3 breadth. Overexpression of MYC significantly restores the growth defect and transcriptional perturbation in SETD1B SET domain mutant cells. In the meantime, the expression of MYC does not rescue the reduced H3K4me3 breadth and RNA polymerase II elongation in SETD1B mutant cells. A disruption of H3K4 demethylase KDM5C enhances global H3K4me3 level and promotes the proliferation of AML cell, and partially rescues the defective cell growth of SETD1B SET domain mutant cells. These data indicate that SETD1B is required for both H3K4me3 breadth and Myc expression to support advanced AML cell proliferation. Thus, a thorough understanding of the SETD1B-mediated H3K4me3 breadth will be critical for the development of markers and therapies for leukemia subtypes that are MYC-dependent.
2025-04-28 | GSE248323 | GEO
Project description:Promoters of many developmentally regulated genes, in the embryonic stem cell state, have a bivalent mark of H3K27me3 and H3K4me3, proposed to confer precise temporal activation upon differentiation. Although Polycomb repressive complex 2 is known to implement H3K27 trimethylation, the COMPASS family member responsible for H3K4me3 at bivalently marked promoters was previously unknown. Here, we identify Mll2 (KMT2b) as the enzyme catalyzing H3K4 trimethylation at bivalently marked promoters in embryonic stem cells. Although H3K4me3 at bivalent genes is proposed to prime future activation, we detected no substantial defect in rapid transcriptional induction after retinoic acid treatment in Mll2-depleted cells. Our identification of the Mll2 complex as the COMPASS family member responsible for H3K4me3 marking at bivalent promoters provides an opportunity to reevaluate and experimentally test models for the function of bivalency in the embryonic stem cell state and in differentiation. ChIP-Seq in mouse embryonic stem (mES) cells for MLL2. ChIP-seq of H3K4me1, H3K4me3 and H3K27me3 for mES cells with RNAi against MLL2(shMLL2) and control (shGFP). ChIP-seq of H3K4me3 in mES cells with RNAi against MLL3 (shMLL3). RNA-seq of mES cells with RNAi against MLL2 and control (shGFP). RNA-seq of control mES cells (shGFP) or MLL2 RNAi mES cells (shMLL2) induced with RA for 6h and 12h.
2013-08-11 | E-GEOD-48172 | biostudies-arrayexpress
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:During DNA replication, histones in nucleosomes ahead of DNA replication forks are evicted and then distributed equally onto leading and lagging strands. Mcm2, a subunit of the replicative MCM helicase, participates in the transfer of parental H3-H4 marked by H3K4me3 to lagging strands. Mutations in Mcm2 (Mcm2-3A) result in enrichment of H3K4me3 at leading strands following DNA replication. Here, we show that mcm2-3A mutant cells partially recover the H3K4me3 lost at lagging strands, with a faster recovery at highly transcribed genes than lowly ones, before mitosis. Furthermore, the H3K4 methyltransferase complex COMPASS is essential in the recovery of H3K4me3, irrespective of transcription status. Finally, H3K4me3 recognition (read) by COMPASS is also important for the restoration (write) of this mark. We suggest that both gene transcription and the “read and write” mechanism contribute to the restoration of H3K4me3, with the later mechanism more important for lowly transcribed chromatin.
2022-04-13 | GSE184188 | GEO
Project description:Trimethylation of histone H3 lysine 4 (H3K4me3) is associated with transcriptional start sites and proposed to regulate transcription initiation. However, redundant functions of the H3K4 SET1/COMPASS methyltransferase complexes complicate elucidation of the specific role of H3K4me3 in transcriptional regulation. Here, by using mouse embryonic stem cells (mESCs) as a model system, we show that acute ablation of shared subunits of the SET1/COMPASS complexes leads to complete loss of all H3K4 methylation. H3K4me3 turnover occurs more rapidly than H3K4me1 and H3K4me2 and is dependent on KDM5 demethylases. Surprisingly, acute loss of H3K4me3 does not have detectable effects on transcriptional initiation but leads to a widespread decrease in transcriptional output, an increase in RNA polymerase II (RNAPII) pausing and slower elongation. Notably, we show that H3K4me3 is required for the recruitment of the Integrator Complex Subunit 11 (INTS11), which is essential for the eviction of paused RNAPII and transcriptional elongation. Thus, our study demonstrates a distinct role for H3K4me3 in transcriptional pause-release and elongation rather than transcriptional initiation.
2023-02-10 | PXD039176 | Pride