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Differential genomic-methylation profile of U937 cells transduced with WT/mutant-DNMT3A

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE90933 | GEO | 2017/12/01

SECONDARY ACCESSION(S): PRJNA356407

REPOSITORIES: GEO

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Differential gene expression profile in U937 cells transduced with WT/mutant-DNMT3A

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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 ‘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.

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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 ‘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

Epigenomic profiling studies of murine leukemia stem cell (LSC) lines established ex vivo by coexpression of R882H-mutated DNMT3A and NRAS-G12D (ChIP-seq)

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 R882H-mutated DNMT3A, H3K4me1, H3K4me3 and H3K27me3 ChIP-seq profiling data of RH-RAS LSCs, and H3K4me1 ChIP-seq data in HOXA9-MEIS1 LSCs.

2016-06-23 | GSE71474 | GEO

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