Differential genomic-methylation profile of EOL-1 cells transduced with WT/mutant-DNMT3A
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE109364 | GEO | 2020/01/31
REPOSITORIES: GEO
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Project description:DNA methyltransferase 3A (DNMT3A) gene is mutated in various myeloid neoplasms including acute myeloid leukemia (AML), especially at the Arg882 and associated with inferior outcomes. Despite the current progress of functional role of DNMT3A mutations, the molecular pathogenesis of myeloid malignancies remains poorly understood. The mechanisms of AML transformation and functional role of DNMT3A mutations through its target genes in the leukemogenesis remain to be explored. Here we wished to perform the differential genomic-methylation profile in U937 cells over-expressed with DNMT3A-Arg882His/Cys (R882H/C) mutations including DNMT3A-WT and vector using Illumina MethylationEPIC BeadChip microarray. Results: Differential genomic-methylation assess identified both hypo- and hypermethylation features in different regions throughout the whole genome of DNMT3A mutants-transduced U937 cells.
2017-12-01 | GSE90933 | GEO
Project description:DNA methyltransferase 3A (DNMT3A) gene is mutated in various myeloid neoplasms including acute myeloid leukemia (AML), especially at the Arg882 and associated with inferior outcomes. Despite the current progress of functional role of DNMT3A mutations, the molecular pathogenesis of myeloid malignancies remains poorly understood. The mechanisms of AML transformation and functional role of DNMT3A mutations through its target genes in the leukemogenesis remain to be explored. Here we wished to perform the differential gene expression profile in U937 cells over-expressed with DNMT3A-Arg882His/Cys (R882H/C) mutations including DNMT3A-WT and vector. Results: Gene expression profiling analysis revealed aberrant expression of several cell-cycle and apoptosis-related genes in U937 cells transduced with mutant DNMT3A compared to WT- or vector control.
2017-12-01 | GSE90931 | GEO
Project description:DNA Methyltransferase 3A (DNMT3A) is frequently mutated in various hematopoietic malignancies. We report that DNMT3A mutational ‘hotspot’ 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. Mechanistically, DNMT3A-R882H induced DNA hypomethylation facilitates gene enhancer/promoter activation. In this dataset, we provided microarray data showing effect of BRD4 inhibitor I-BET151 on gene expression in leukemic stem cells transformed by DNMT3A R882H and NRAS G12D.
2019-06-12 | GSE130634 | GEO
Project description:Purpose: DNA methyltransferase 3A (DNMT3A) mediates de novo DNA methylation. Mutations in DNMT3A are associated with hematological malignancies, most frequently acute myeloid leukemia. DNMT3A mutations are hypothesized to establish a pre-leukemic state, rendering cells vulnerable to secondary oncogenic mutations and malignant transformation. However, the mechanisms by which DNMT3A mutations contribute to leukemogenesis are not well-defined. Methods: Methylated DNA immunoprecipitation (MeDIP) was used to detect regional differences in DNA methylation between DNMT3A WT and MT clones. DNA extraction of WTblk, WT1, MT1, MT2, and MT4 cell lines was performed as previously described. 5-mC profiling, fragmentation, library preparation and sequencing were performed by Otogenetics (Atlanta, GA, USA). In brief, paired-end libraries were generated using the Illumina TruSeq DNA sample preparation kit. Illumina HiSeq2500 was used for sequencing with a paired-end sequencing length of 100-125 bp and approximately 40 million reads per sample. Results: We attempted to identify differentially methylated genes based on DNMT3A mutation status and found very few regions of differential methylation between WT and MT cell lines (Figure 3C), which did not exceed the number of regions expected to exhibit differential methylation by chance alone. These data suggest that regional methylation patterns do not differ between DNMT3A MT and WT cell lines in our gene-edited K562 cells. Conclusions: CRISPR/Cas9-mediated DNMT3A-mutated K562 cells may be used to model effects of DNMT3A mutations in human cells. Our findings implicate aberrant splicing and induction of genomic instability as potential mechanisms by which DNMT3A mutations might predispose to malignancy.
2018-01-09 | GSE96577 | GEO
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: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:DNA Methyltransferase 3A (DNMT3A) is frequently mutated in various hematopoietic malignancies; however, the underlying oncogenic mechanisms remain elusive. Here, we report that DNMT3A mutational ‘hotspot’ 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 ‘stemness’ 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.
2016-06-23 | GSE71472 | GEO
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 ‘hotspot’ 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 ‘stemness’ 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.
2016-06-23 | GSE71437 | GEO