Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA168371 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:DNA methyltransferase 3A (DNMT3A) is frequently mutated in hematological cancers; however, the underlying oncogenic mechanism remains elusive. Here, we report that DNMT3A mutational hotspot at Arg882 (DNMT3A R882H) cooperates with NRAS mutation to transform hematopoietic stem/progenitor cells and induce acute leukemia development. Mechanistically, DNMT3A R882H directly binds to and potentiates transactivation of stemness genes critical for leukemogenicity including Meis1, Mn1 and Hoxa gene cluster. DNMT3A R882H induces focal epigenetic alterations, including CpG hypomethylation and concurrent gain of active histone modifications, at cis-regulatory elements such as enhancers to facilitate gene transcription. CRISPR/Cas9-mediated ablation of a putative Meis1 enhancer carrying DNMT3A R882H-induced DNA hypomethylation impairs Meis1 expression. Importantly, DNMT3A R882H-induced gene expression programs can be repressed through Dot1l inhibition, providing an attractive therapeutic strategy for DNMT3A-mutated leukemias. This SuperSeries is composed of the SubSeries listed below.
2016-06-23 | GSE71475 | GEO
Project description:Establishment of the DNA methylation landscape of mammalian oocytes, mediated by the DNMT3A-DNMT3L complex, is crucial for reproduction and development. In mouse oocytes, high levels of DNA methylation occur exclusively in the transcriptionally active regions, with moderate to low levels of methylation in other regions. Histone H3K36me3 mediates the high levels of methylation in the transcribed regions; however, it is unknown which histone mark guides the methylation in the other regions. Here, we show that, in mouse oocytes, H3K36me2 is highly enriched in the X chromosome and is broadly distributed across all autosomes. Upon H3K36me2 depletion, DNA methylation in moderately methylated regions is selectively affected, and a methylation pattern unique to the X chromosome is switched to an autosome-like pattern. Furthermore, we find that simultaneous depletion of H3K36me2 and H3K36me3 results in global hypomethylation, comparable to that of DNMT3A depletion. Therefore, the two histone marks jointly provide the chromatin platform essential for guiding DNMT3A-dependent DNA methylation in mouse oocytes.
2022-07-07 | GSE183969 | GEO
Project description:Escape from X chromosome inactivation occurs within topologically associated domains
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Project description:DNA Methyltransferase 3A (DNMT3A) is frequently mutated in various hematopoietic malignancies; however, the underlying oncogenic mechanisms remain elusive. Here, we report that DNMT3A mutational âhotspotâ at Arg882 (DNMT3A-R882H) cooperates with constitutively activated RAS in transforming murine hematopoietic stem/progenitor cells (HSPCs) ex vivo and inducing acute leukemias in vivo. DNMT3A-R882H potentiates aberrant transactivation of âstemnessâ gene expression programs, notably transcription factors Meis1, Hox-A, Mn1 and Mycn. Mechanistically, R882-mutated DNMT3A directly binds to cis-regulatory elements of these genes and induces focal CpG hypomethylation reminiscent of what was seen in human leukemias bearing DNMT3A R882 mutation. Furthermore, DNMT3A-R882H induced DNA hypomethylation facilitates gene enhancer/promoter activation and recruitment of Dot1l-associated transcription elongation machineries. Inactivation of Dot1l represses DNMT3AR882H-mediated stem cell gene dysregulation and acute leukemogenicity. In this dataset, we provided enhanced Reduced Representation Bisulfite Sequencing (eRRBS) DNA methylome profiling data showing effect of DNMT3A R882H mutation or WT expression on hematopoietic stem/progenitor cells with NRAS G12D co-transduction. eRRBBs DNA methylome analysis of Lin- enriched hematopoietic stem/progenitor cells with retroviral infection of NRAS G12D alone (EV-RAS), DNMT3A R882H with NRAS G12D (RH-RAS) or DNMT3A WT with NRAS G12D (WT-RAS) at day 16 post-transduction.
2016-06-23 | E-GEOD-71473 | biostudies-arrayexpress
Project description:DNA Methyltransferase 3A (DNMT3A) is frequently mutated in various hematopoietic malignancies; however, the underlying oncogenic mechanisms remain elusive. Here, we report that DNMT3A mutational âhotspotâ at Arg882 (DNMT3A-R882H) cooperates with constitutively activated RAS in transforming murine hematopoietic stem/progenitor cells (HSPCs) ex vivo and inducing acute leukemias in vivo. DNMT3A-R882H potentiates aberrant transactivation of âstemnessâ gene expression programs, notably transcription factors Meis1, Hox-A, Mn1 and Mycn. Mechanistically, R882-mutated DNMT3A directly binds to cis-regulatory elements of these genes and induces focal CpG hypomethylation reminiscent of what was seen in human leukemias bearing DNMT3A R882 mutation. Furthermore, DNMT3A-R882H induced DNA hypomethylation facilitates gene enhancer/promoter activation and recruitment of Dot1l-associated transcription elongation machineries. Inactivation of Dot1l represses DNMT3AR882H-mediated stem cell gene dysregulation and acute leukemogenicity. In this dataset, we provided H3K4me1, H3K27ac and H3K79me2 ChIP-seq profiling data showing effect of DNMT3A R882H mutation or WT expression on epigenetic landscapes of hematopoietic stem/progenitor cells with NRAS G12D co-transduction. ChIP-seq analysis of Lin- enriched hematopoietic stem/progenitor cells with retroviral infection of NRAS G12D alone (EV-RAS), DNMT3A R882H with NRAS G12D (RH-RAS) or DNMT3A WT with NRAS G12D (WT-RAS) 3 weeks post-transduction. Antibodies of H3K4me1, H3K27ac and H3K79me2 were used.
2016-06-23 | E-GEOD-71472 | biostudies-arrayexpress
Project description:DNA Methyltransferase 3A (DNMT3A) is frequently mutated in various hematopoietic malignancies; however, the underlying oncogenic mechanisms remain elusive. Here, we report that DNMT3A mutational â??hotspotâ?? at Arg882 (i.e., DNMT3A-R882H) cooperates with constitutively activated RAS in transforming murine hematopoietic stem/progenitor cells (HSPCs) ex vivo and inducing acute leukemias in vivo. DNMT3A-R882H potentiates aberrant transactivation of â??stemnessâ?? gene expression programs, notably transcription factors Meis1, Hox-A, Mn1 and Mycn. Mechanistically, R882-mutated DNMT3A directly binds to cis-regulatory elements of these genes and induces focal CpG hypomethylation reminiscent of what was seen in human leukemias bearing DNMT3A R882 mutation. Furthermore, DNMT3A-R882H induced DNA hypomethylation facilitates gene enhancer/promoter activation and recruitment of Dot1l-associated transcription elongation machineries. Inactivation of Dot1l represses DNMT3AR882H-mediated stem cell gene dysregulation and acute leukemogenicity. In this dataset, we provided microarray data showing effect of R882H-mutated or WT DNMT3A on gene expression among HSPCs with NRAS G12D co-transduction. Microarray analysis of Lin- enriched hematopoietic stem/progenitor cells with retroviral infection of NRAS G12D alone (EV-RAS), DNMT3A R882H with NRAS G12D (RH-RAS) or DNMT3A WT with NRAS G12D (WT-RAS) at day 12 or day 16 post-transduction.
2016-06-23 | E-GEOD-71437 | biostudies-arrayexpress
Project description:Cancer is characterized by hypomethylation-associated silencing of large chromatin domains, whose contribution to tumorigenesis is uncertain. Through high-resolution single cell DNA methylation sequencing in prostate cancer, we identify 40 core hypomethylation domains, consistently hypomethylated across tumor cells and arising at early stages of malignancy. Transcriptionally silenced genes within these domains are enriched for immune-related genes; nested among repressive domains are small loci with preserved methylation, encoding cell proliferation genes that escape silencing. Prominent among hypomethylation-silenced genes is a gene cluster harboring all five CD1 genes that present lipid antigens to NKT cells, and four IFI16-related interferon-inducible genes implicated in innate immunity. Re-expression of CD1 or IFI16 murine orthologs in immunocompetent mice abrogates prostate tumorigenesis, accompanied by activation of anti-tumor immunity. Thus, early epigenetic changes in cancer may shape tumorigenesis, targeting co-located genes within defined chromosomal loci. Hypomethylation domains are detectable in blood specimens enriched for circulating tumor cells.
2023-06-14 | GSE208448 | GEO
Project description:Cancer is characterized by hypomethylation-associated silencing of large chromatin domains, whose contribution to tumorigenesis is uncertain. Through high-resolution single cell DNA methylation sequencing in prostate cancer, we identify 40 core hypomethylation domains, consistently hypomethylated across tumor cells and arising at early stages of malignancy. Transcriptionally silenced genes within these domains are enriched for immune-related genes; nested among repressive domains are small loci with preserved methylation, encoding cell proliferation genes that escape silencing. Prominent among hypomethylation-silenced genes is a gene cluster harboring all five CD1 genes that present lipid antigens to NKT cells, and four IFI16-related interferon-inducible genes implicated in innate immunity. Re-expression of CD1 or IFI16 murine orthologs in immunocompetent mice abrogates prostate tumorigenesis, accompanied by activation of anti-tumor immunity. Thus, early epigenetic changes in cancer may shape tumorigenesis, targeting co-located genes within defined chromosomal loci. Hypomethylation domains are detectable in blood specimens enriched for circulating tumor cells.
2023-06-14 | GSE208447 | GEO
Project description:Cancer is characterized by hypomethylation-associated silencing of large chromatin domains, whose contribution to tumorigenesis is uncertain. Through high-resolution single cell DNA methylation sequencing in prostate cancer, we identify 40 core hypomethylation domains, consistently hypomethylated across tumor cells and arising at early stages of malignancy. Transcriptionally silenced genes within these domains are enriched for immune-related genes; nested among repressive domains are small loci with preserved methylation, encoding cell proliferation genes that escape silencing. Prominent among hypomethylation-silenced genes is a gene cluster harboring all five CD1 genes that present lipid antigens to NKT cells, and four IFI16-related interferon-inducible genes implicated in innate immunity. Re-expression of CD1 or IFI16 murine orthologs in immunocompetent mice abrogates prostate tumorigenesis, accompanied by activation of anti-tumor immunity. Thus, early epigenetic changes in cancer may shape tumorigenesis, targeting co-located genes within defined chromosomal loci. Hypomethylation domains are detectable in blood specimens enriched for circulating tumor cells.
2023-06-14 | GSE210260 | GEO
Project description:Cancer is characterized by hypomethylation-associated silencing of large chromatin domains, whose contribution to tumorigenesis is uncertain. Through high-resolution single cell DNA methylation sequencing in prostate cancer, we identify 40 core hypomethylation domains, consistently hypomethylated across tumor cells and arising at early stages of malignancy. Transcriptionally silenced genes within these domains are enriched for immune-related genes; nested among repressive domains are small loci with preserved methylation, encoding cell proliferation genes that escape silencing. Prominent among hypomethylation-silenced genes is a gene cluster harboring all five CD1 genes that present lipid antigens to NKT cells, and four IFI16-related interferon-inducible genes implicated in innate immunity. Re-expression of CD1 or IFI16 murine orthologs in immunocompetent mice abrogates prostate tumorigenesis, accompanied by activation of anti-tumor immunity. Thus, early epigenetic changes in cancer may shape tumorigenesis, targeting co-located genes within defined chromosomal loci. Hypomethylation domains are detectable in blood specimens enriched for circulating tumor cells.
2023-06-14 | GSE209967 | GEO