The catalytic domain of SETD1B regulates H3K4me3 breadth and Myc expression in MLL-r leukemia (ChIP-seq_mus)
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PROVIDER: PRJNA1043213 | ENA |
REPOSITORIES: ENA
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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: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 | 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 | GSE248318 | GEO
Project description:The catalytic domain of SETD1B regulates H3K4me3 breadth and Myc expression in MLL-r leukemia
| PRJNA1043212 | ENA
Project description:The catalytic domain of SETD1B regulates H3K4me3 breadth and Myc expression in MLL-r leukemia (CUT&Tag)
| PRJNA1043206 | ENA
Project description:The catalytic domain of SETD1B regulates H3K4me3 breadth and Myc expression in MLL-r leukemia (ChIP-seq_human)
| PRJNA1043208 | ENA
Project description:The catalytic domain of SETD1B regulates H3K4me3 breadth and Myc expression in MLL-r leukemia (RNA-seq)
| PRJNA1043214 | ENA
Project description:Histone 3 lysine 4 trimethylation (H3K4me3) is an epigenetic mark found at active gene promoters and CpG islands. H3K4me3 is essential for mammalian development, yet mechanisms underlying its genomic targeting are poorly understood. H3K4me3 methyltransferases SETD1B and MLL2 are essential for oogenesis. We investigated changes in H3K4me3 in Setd1b conditional knockout (cKO) GV oocytes using ultra-low input ChIP-seq, in complement to DNA methylation and gene expression analysis. Setd1b cKO oocytes showed a redistribution of H3K4me3, with a marked loss at active gene promoters associated with downregulated gene expression. Remarkably, many regions gained H3K4me3 in Setd1b cKOs, in particular those that were DNA hypomethylated, transcriptionally inactive and CpG-rich. All of these are hallmarks of MLL2 targets; thus, loss of SETD1B appears to enable enhanced MLL2 activity. Our work reveals two distinct, complementary mechanisms of genomic targeting of H3K4me3 in oogenesis, with SETD1B linked to transcriptional activity and MLL2 to CpG content.
2022-01-17 | GSE167986 | GEO
Project description:Histone 3 lysine 4 trimethylation (H3K4me3) is an epigenetic mark found at active gene promoters and CpG islands. H3K4me3 is essential for mammalian development, yet mechanisms underlying its genomic targeting are poorly understood. H3K4me3 methyltransferases SETD1B and MLL2 are essential for oogenesis. We investigated changes in H3K4me3 in Setd1b conditional knockout (cKO) GV oocytes using ultra-low input ChIP-seq, in complement to DNA methylation and gene expression analysis. Setd1b cKO oocytes showed a redistribution of H3K4me3, with a marked loss at active gene promoters associated with downregulated gene expression. Remarkably, many regions gained H3K4me3 in Setd1b cKOs, in particular those that were DNA hypomethylated, transcriptionally inactive and CpG-rich. All of these are hallmarks of MLL2 targets; thus, loss of SETD1B appears to enable enhanced MLL2 activity. Our work reveals two distinct, complementary mechanisms of genomic targeting of H3K4me3 in oogenesis, with SETD1B linked to transcriptional activity and MLL2 to CpG content.
2022-01-17 | GSE167985 | GEO