Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA383551 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5457930.fastq.gz | Fastqsanger.gz | |||
| SRR5457931.fastq.gz | Fastqsanger.gz | |||
| SRR5457922.fastq.gz | Fastqsanger.gz | |||
| SRR5457932.fastq.gz | Fastqsanger.gz | |||
| SRR5457923.fastq.gz | Fastqsanger.gz |
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Project description:Loss of Setd1b in adult mice using both ubiquitous and hematopoietic-specific deletion strategies caused lethality arising from severe hematopoietic defects. To identify genes regulated by Setd1b in HSPCs we performed RNA-seq analysis of the LSK (Lin-, Sca+, Kit+) compartment in the bone marrow. Mice carrying heterozygous and homozygous conditional Setd1b alleles and Rosa26-Cre-ERT2 were treated with Tamoxifen for 6 days (4 days gavage - 3 days pause - 2 days gavage). Mice were sacrificed 3 days after the last treatment and RNA was isolated and processed for next generation sequencing. We found that Setd1b regulates key lineage specification components including Cebpa, Gata-1 and Klf-1.
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Project description:We have analyzed changes in histone 3 lysine 4 methylation (H3K4me3 and H3K4me1), histone acetylation (H3K9ac and H3K27ac) and gene expression resulting from Setd1b knockdown in adult hippocampal CA neurons in mice. We implemented Cre/loxP-mediated conditional knockout strategy in order to knockdown this histone methyltransferase in excitatory forebrain neurons in adult mice.
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Project description:Germ cell development involves major reprogramming of the epigenome to prime the zygote for totipotency. Histone 3 lysine 4 (H3K4) methylations are universal epigenetic marks mediated in mammals by six H3K4 methyltransferases related to fly Trithorax, including two yeast Set1 orthologs: Setd1a and Setd1b. Whereas Setd1a plays no role in oogenesis, we report that Setd1b deficiency causes female sterility. Oocyte specific Gdf9iCre conditional knockout (Setd1bGdf9cKO) ovaries develop through all stages however follicular loss accumulated with age and unfertilized metaphase II (MII) oocytes exhibited irregularities of the zona pellucida and meiotic spindle. Most Setd1bGdf9cKO zygotes remained in the pronuclear stage and displayed polyspermy in the perivitelline space. Expression profiling of Setd1bGdf9cKO MII oocytes revealed (i) that Setd1b promotes the expression of the major oocyte transcription factors including Obox1, 2, 5, 7, Meis2 and Sall4; and (ii) two-times more up- than downregulated mRNAs suggesting that Setd1b also promotes the expression of negative regulators of oocyte development with multiple Zfp-KRAB factors implicated. Together, these findings indicate that Setd1b serves as maternal effect gene through regulation of the oocyte gene expression program.
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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.
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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 | 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.
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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.
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Project description:Setd2, the histone H3 lysine 36 methyltransferase, plays an important role in the pathogenesis of hematologic malignancies. The research on the role of Setd2 in leukemogenesis has made great progress, but its role in MDS is still unknown. Here, we knock out Setd2 in the NUP98-HOXD13 transgenic (NHD13 Tg) mouse, and demonstrate that loss of Setd2 accelerates the transformation of MDS into AML. The conditional deletion of Setd2 also interferes the differentiation of hematopoietic stem and progenitor cells (HSPCs), and results in the decrease of granulocyte monocyte progenitor (GMP) cells, increase of megakaryocyte erythroid progenitor (MEP) cells and common myeloid progenitor (CMP) cells. Loss of Setd2 impairs erythroid differentiation, includes cell cycle arrest in G2-M and enhances the selt-renewal ability of HSPCS. Our RNA-seq,ChIP-seq and WGBS analysis indicats that S100A8 and S100A9 are direct target genes of H3K36me3 and expression of heterodimeric S100 calcium-binding proteins S100A8 and S100A9 are downregulated in HSPCs when Setd2 deficiency. Addition of recombinant S100A8 or S100A9 weakens the clonogenic progenitors of Setd2 deficient HSPCs. Therefore, our results demonstrate that loss of Setd2 promotes the transformation of MDS into AML, which proves Setd2 as a tumor suppressor in MDS, and provides a potential therapeutic target for MDS associated leukemia.
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Project description:Despite correlations between histone methyltransferase (HMT) activity and gene regulation, direct evidence that HMT activity is responsible for gene activation is sparse. We address the role of the HMT activity for MLL1, a histone H3 lysine 4 (H3K4) methyltransferase critical for maintaining hematopoietic stem cells (HSCs). Here we show that the SET domain and thus HMT activity of MLL1 is dispensable for maintaining HSCs and for supporting leukemogenesis driven by the MLL-AF9 fusion oncoprotein. Upon Mll1 deletion, histone H4 lysine 16 (H4K16) acetylation was selectively depleted at MLL1 target genes in conjunction with reduced transcription. Surprisingly, inhibition of SIRT1 was sufficient to prevent the loss of H4K16 acetylation and the reduction in MLL1 target gene expression. Thus, recruited MOF activity, and not the intrinsic HMT activity of MLL1, is central for the maintenance of HSC target genes. In addition, this work reveals a role for SIRT1 in opposing MLL1 function. 11 Samples, 5 controls and 5 KOs with antibodies H3K4me1, H3K4me3, and H3K27Ac. One input Sample.
2014-04-03 | E-GEOD-56456 | biostudies-arrayexpress