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Hoxa5 undergoes dynamic DNA methylation and transcriptional repression in the adipose tissue of mice exposed to high-fat diet
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Hoxa5 undergoes dynamic DNA methylation and transcriptional repression in the adipose tissue of mice exposed to high-fat diet
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Journal Article
Hoxa5 undergoes dynamic DNA methylation and transcriptional repression in the adipose tissue of mice exposed to high-fat diet
2016
Overview
Background/Objectives:
The genomic bases of the adipose tissue abnormalities induced by chronic positive calorie excess have been only partially elucidated. We adopted a genome-wide approach to directly test whether long-term high-fat diet (HFD) exposure affects the DNA methylation profile of the mouse adipose tissue and to identify the functional consequences of these changes.
Subjects/Methods:
We have used epididymal fat of mice fed either high-fat (HFD) or regular chow (STD) diet for 5 months and performed genome-wide DNA methylation analyses by methylated DNA immunoprecipitation sequencing (MeDIP-seq). Mouse Homeobox (
Hox
) Gene DNA Methylation PCR, RT-qPCR and bisulphite sequencing analyses were then performed.
Results:
Mice fed the HFD progressively expanded their adipose mass accompanied by a significant decrease in glucose tolerance (
P
<0.001) and insulin sensitivity (
P
<0.05). MeDIP-seq data analysis revealed a uniform distribution of differentially methylated regions (DMR) through the entire adipocyte genome, with a higher number of hypermethylated regions in HFD mice (
P
<0.005). This different methylation profile was accompanied by increased expression of the
Dnmt3a
DNA methyltransferase (Dnmt;
P
<0.05) and the methyl-CpG-binding domain protein
Mbd3
(
P
<0.05) genes in HFD mice. Gene ontology analysis revealed that, in the HFD-treated mice, the
Hox
family of development genes was highly enriched in differentially methylated genes (
P
=0.008). To validate this finding,
Hoxa5
, which is implicated in fat tissue differentiation and remodeling, has been selected and analyzed by bisulphite sequencing, confirming hypermethylation in the adipose tissue from the HFD mice.
Hoxa5
hypermethylation was associated with downregulation of
Hoxa5
mRNA and protein expression. Feeding animals previously exposed to the HFD with a standard chow diet for two further months improved the metabolic phenotype of the animals, accompanied by return of
Hoxa5
methylation and expression levels (
P
<0.05) to values similar to those of the control mice maintained under standard chow.
Conclusions:
HFD induces adipose tissue abnormalities accompanied by epigenetic changes at the
Hoxa5
adipose tissue remodeling gene.
Publisher
Nature Publishing Group UK,Nature Publishing Group
