RRC ID 80090
Author Yao S, Prates K, Freydenzon A, Assante G, McRae AF, Morris MJ, Youngson NA.
Title Liver-specific deletion of de novo DNA methyltransferases protects against glucose intolerance in high-fat diet-fed male mice.
Journal FASEB J
Abstract Alterations to gene transcription and DNA methylation are a feature of many liver diseases including fatty liver disease and liver cancer. However, it is unclear whether the DNA methylation changes are a cause or a consequence of the transcriptional changes. It is even possible that the methylation changes are not required for the transcriptional changes. If DNA methylation is just a minor player in, or a consequence of liver transcriptional change, then future studies in this area should focus on other systems such as histone tail modifications. To interrogate the importance of de novo DNA methylation, we generated mice that are homozygous mutants for both Dnmt3a and Dnmt3b in post-natal liver. These mice are viable and fertile with normal sized livers. Males, but not females, showed increased adipose depots, yet paradoxically, improved glucose tolerance on both control diet and high-fat diets (HFD). Comparison of the transcriptome and methylome with RNA sequencing and whole-genome bisulfite sequencing in adult hepatocytes revealed that widespread loss of methylation in CpG-rich regions in the mutant did not induce loss of homeostatic transcriptional regulation. Similarly, extensive transcriptional changes induced by HFD did not require de novo DNA methylation. The improved metabolic phenotype of the Dnmt3a/3b mutant mice may be mediated through the dysregulation of a subset of glucose and fat metabolism genes which increase both glucose uptake and lipid export by the liver. However, further work is needed to confirm this.
Volume 38(10)
Pages e23690
Published 2024-5-31
DOI 10.1096/fj.202301546RR
PMID 38795327
MeSH Animals DNA (Cytosine-5-)-Methyltransferases* / genetics DNA (Cytosine-5-)-Methyltransferases* / metabolism DNA Methylation* DNA Methyltransferase 3A* / metabolism DNA Methyltransferase 3B* Diet, High-Fat* / adverse effects Female Glucose Intolerance* / genetics Glucose Intolerance* / metabolism Liver* / metabolism Male Mice Mice, Inbred C57BL
Mice RBRC03731 RBRC03733