Transcriptomic alterations including p53 pathway dysregulation prime DNMT3A mutant cells for transformation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1151635 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR30355527_1.fastq.gz | Fastqsanger.gz | |||
| SRR30355527_2.fastq.gz | Fastqsanger.gz | |||
| SRR30355531_1.fastq.gz | Fastqsanger.gz | |||
| SRR30355531_2.fastq.gz | Fastqsanger.gz |
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Project description:DNA methyltransferase 3A (DNMT3A) is the most frequently mutated gene in clonal hematopoiesis (CH) and serves as a key tumor suppressor in the hematopoietic system. Somatic mutations in DNMT3A arise in hematopoietic stem and progenitor cells (HSPCs) many years before malignancies develop, but how they prime cells for transformation remains unknown, partly due to our inability to compare mutant to equivalent wild-type cells before frank disease. To overcome this challenge, we derived multiple normal and DNMT3A-mutant lymphoblastoid cell clones from a germ-line mosaic individual in whom these cells co-existed for nearly six decades. Although arising early in gestation, mutant cells dominated the blood, but not other tissues. Deep sequencing revealed similar mutational burdens and mutational signatures across normal and mutant clones. In contrast, epigenetic profiling uncovered focal erosion of DNA methylation at oncogenic regulatory regions in mutant clones. These regions overlapped with those sensitive to DNMT3A loss after DNMT3A ablation in HSPCs and with those present in leukemia samples. These results suggest that DNMT3A is responsible for maintaining a conserved DNA methylation pattern that is maintained for decades and across cell types and states. Erosion of this pattern confers a distinct competitive advantage, increasing the likelihood of malignant transformation
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Project description:DNA methylation by de novo DNA methyltransferases 3A (DNMT3A) and 3B (DNMT3B) is essential for genome regulation and development. Dysregulation of this process is implicated in various diseases, notably cancer. However, the mechanisms underlying DNMT3 substrate recognition and enzymatic specificity remain elusive. Here we report a 2.65-Å crystal structure of the DNMT3A-DNMT3L-DNA complex where two DNMT3A monomers simultaneously attack two CpG dinucleotides, with the target sites separated by fourteen base pairs within the same DNA duplex. The DNMT3A-DNA interaction involves a target recognition domain (TRD), a catalytic loop and DNMT3A homodimeric interface. A TRD residue Arg836 makes crucial contact with CpG, ensuring DNMT3A enzymatic preference towards CpG sites in cells. Hematological cancer-associated somatic mutations at the substrate-binding sites decrease DNMT3A activity, induce CpG hypomethylation and promote transformation of hematopoietic cells. Together, our study reveals the mechanistic basis for DNMT3A-mediated DNA methylation and establishes its etiologic link to human disease.
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Project description:Dnmt3a Regulates T-cell Development and Suppresses T-ALL Transformation
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Project description:DNA methylation by de novo DNA methyltransferases 3A (DNMT3A) and 3B (DNMT3B) is essential for genome regulation and development. Dysregulation of this process is implicated in various diseases, notably cancer. However, the mechanisms underlying DNMT3 substrate recognition and enzymatic specificity remain elusive. Here we report a 2.65-Å crystal structure of the DNMT3A-DNMT3L-DNA complex where two DNMT3A monomers simultaneously attack two CpG dinucleotides, with the target sites separated by fourteen base pairs within the same DNA duplex. The DNMT3A-DNA interaction involves a target recognition domain (TRD), a catalytic loop and DNMT3A homodimeric interface. A TRD residue Arg836 makes crucial contact with CpG, ensuring DNMT3A enzymatic preference towards CpG sites in cells. Hematological cancer-associated somatic mutations at the substrate-binding sites decrease DNMT3A activity, induce CpG hypomethylation and promote transformation of hematopoietic cells. Together, our study reveals the mechanistic basis for DNMT3A-mediated DNA methylation and establishes its etiologic link to human disease.
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Project description:DNA methylation by de novo DNA methyltransferases 3A (DNMT3A) and 3B (DNMT3B) is essential for genome regulation and development. Dysregulation of this process is implicated in various diseases, notably cancer. However, the mechanisms underlying DNMT3 substrate recognition and enzymatic specificity remain elusive. Here we report a 2.65-Å crystal structure of the DNMT3A-DNMT3L-DNA complex where two DNMT3A monomers simultaneously attack two CpG dinucleotides, with the target sites separated by fourteen base pairs within the same DNA duplex. The DNMT3A-DNA interaction involves a target recognition domain (TRD), a catalytic loop and DNMT3A homodimeric interface. A TRD residue Arg836 makes crucial contact with CpG, ensuring DNMT3A enzymatic preference towards CpG sites in cells. Hematological cancer-associated somatic mutations at the substrate-binding sites decrease DNMT3A activity, induce CpG hypomethylation and promote transformation of hematopoietic cells. Together, our study reveals the mechanistic basis for DNMT3A-mediated DNA methylation and establishes its etiologic link to human disease.
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