Constitutive loss of DNMT3A causes morbid obesity through misregulation of adipogenesis
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- Evaluated articles (eLife)
- Cell Biology (eLife)
Abstract
DNA Methyltransferase 3A (DNMT3A) is an important facilitator of differentiation of both embryonic and hematopoietic stem cells. Heterozygous germline mutations in DNMT3A lead to Tatton-Brown-Rahman Syndrome (TBRS), characterized by obesity and excessive height. While DNMT3A is known to impact feeding behavior via the hypothalamus, here we investigated a role in adipocyte progenitors utilizing heterozygous knockout mice that recapitulate cardinal TBRS phenotypes. These mice become morbidly obese due to adipocyte enlargement and tissue expansion. Adipose tissue in these mice exhibited defects in preadipocyte maturation and precocious activation of inflammatory gene networks, including interleukin-6 signaling. Adipocyte progenitor cell lines lacking DNMT3A exhibited aberrant differentiation. Furthermore, mice in which Dnmt3a was specifically ablated in adipocyte progenitors showed enlarged fat depots and increased progenitor numbers, partly recapitulating the TBRS obesity phenotypes. Loss of DNMT3A led to constitutive DNA hypomethylation, such that the DNA methylation landscape of young adipocyte progenitors resemble that of older wild-type mice. Together, our results demonstrate that DNMT3A coordinates both the central and local control of energy storage required to maintain normal weight and prevent inflammatory obesity.
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Evaluation Summary:
This manuscript employs a diverse array of approaches including single cell RNA sequencing, bioinformatic analyses, and whole genome bisulfite sequencing to propose a mechanism underlying their findings that will interest scientists broadly in fields of metabolism, development, and epigenetics.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Joint Public Review:
This is a well written paper that addresses an area of broad interest to researchers studying metabolism, development, and epigenetics. Strengths of this manuscript include the generation of a new mouse model that appears to recapitulate features of a human genetic disorder. The authors also employ a diverse array of approaches including single cell RNA sequencing, bioinformatic analyses, and whole genome bisulfite sequencing to propose a mechanism underlying their findings. Weaknesses of the manuscript include incomplete metabolic phenotyping of the mouse models and an over-reliance on correlative findings related to their transcriptomic and genomic studies. Addressing these limitations is necessary to provide further confidence that the findings here justify the conclusions made.
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