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Hematologic DNMT3A Reduction and High Fat Diet Synergize to Promote Weight Gain and Tissue Inflammation

ABSTRACT: Hematologic DNMT3A Reduction and High Fat Diet Synergize to Promote Weight Gain and Tissue Inflammation

PROVIDER: PRJNA858103 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR20110602_1.fastq.gz	Fastqsanger.gz
	SRR20110602_2.fastq.gz	Fastqsanger.gz
	SRR20110603_1.fastq.gz	Fastqsanger.gz
	SRR20110603_2.fastq.gz	Fastqsanger.gz
	SRR20110604_1.fastq.gz	Fastqsanger.gz

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Hematologic DNMT3A Reduction and High Fat Diet Synergize to Promote Weight Gain and Tissue Inflammation

Project description:In the aging hematopoietic system, blood cell production becomes dominated by a limited number of hematopoietic stem cell (HSC) clones. While somatic mutations in the de novo DNA methyltransferase 3A (DNMT3A) frequently drive clone dominance, the aging milieu also likely contributes to selection of variant HSCs. The detrimental impact of clonal hematopoiesis on organismal health is thought to be mediated by differentiated progeny of variant HSCs through mechanisms as yet poorly understood. Here, we examined the interaction between high fat diet (HFD) as an inflammatory stressor and a hematopoietic system haploinsufficient for DNMT3A. Strikingly, HFD accelerated weight gain in mice harboring bone marrow with reduced DNMT3A. Moreover, distal tissues of such mice including pancreas, adipose, and spleen, harbored high levels of mutant macrophages that impacted tissue function. Aberrant DNA methylation and pro-inflammatory transcriptional activation in mutant-derived myeloid cells correlated with increased IL-6 and TNFa signaling. Together, these findings identify synergism between HFD and DNMT3A haploinsufficiency that, through increased inflammatory myeloid cell functions, can contribute to deterioration in organismal health.

2024-01-01 | GSE208075 | GEO

Hematologic DNMT3A reduction and high-fat diet synergize to promote weight gain and tissue inflammation.

Project description:During aging, blood cell production becomes dominated by a limited number of variant hematopoietic stem cell (HSC) clones. Differentiated progeny of variant HSCs are thought to mediate the detrimental effects of such clonal hematopoiesis on organismal health, but the mechanisms are poorly understood. While somatic mutations in DNA methyltransferase 3A (DNMT3A) frequently drive clonal dominance, the aging milieu also likely contributes. Here, we examined in mice the interaction between high-fat diet (HFD) and reduced DNMT3A in hematopoietic cells; strikingly, this combination led to weight gain. HFD amplified pro-inflammatory pathways and upregulated inflammation-associated genes in mutant cells along a pro-myeloid trajectory. Aberrant DNA methylation during myeloid differentiation and in response to HFD led to pro-inflammatory activation and maintenance of stemness genes. These findings suggest that reduced DNMT3A in hematopoietic cells contributes to weight gain, inflammation, and metabolic dysfunction, highlighting a role for DNMT3A loss in the development of metabolic disorders.

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Antipsychotic Weight Gain

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Systematic profiling of DNMT3A variants reveals protein instability mediated by the DCAF8 E3 ubiquitin ligase adaptor

Project description:Clonal hematopoiesis is a prevalent age-related condition associated with greatly increased risk of hematologic malignancies. Mutations in DNA methyltransferase 3A (DNMT3A) are the most common drivers of this state and contribute to multiple types of hematologic malignancy. DNMT3A variants occur across the gene and some are associated with particular disease states, but the functional relevance and mechanisms of pathogenesis of the majority of the mutations is unknown. Here, we systematically investigated the methyltransferase activity and protein stability of 253 disease-associated DNMT3A mutations, finding that 74% were loss-of-function mutations. Nearly half of these variants exhibited reduced protein stability and, as a class, correlated with greater clonal expansion and AML development. To identify the mechanisms underlying the instability, we conducted a CRISPR screen and uncovered regulated destruction of DNMT3A mediated by the DCAF8 E3 ubiquitin ligase adaptor. We establish a new paradigm to classify novel variants that has prognostic and therapeutic significance for patients with hematologic disease.

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