High fat diet induces chromatin remodelling and alters the expression of the diabetogene Ped/Pea-15

Environmental factors interact with the genome to influence gene expression, tissue function and also disease risk. External stimuli may affect the phenotype through epigenetic mechanisms that provide an interface with the genome. Phosphoprotein Enriched in Diabetes/ Phosphoprotein Enriched in Astrocytes (Ped/Pea-15) is a gene commonly overexpressed in Type 2 Diabetes individuals and in their euglycaemic offspring. Furthermore, its overexpression impairs glucose tolerance and insulin sensitivity in transgenic mouse models. However, whether external cues can affect its expression remains unclear. Therefore, the aim of this study is to evaluate whether the administration of a high fat diet (HFD) in mice could affect Ped/Pea-15 expression and whether chromatin remodelling and epigenetic modifications take part in this regulation. In this work, I demonstrated that high fat diet increases Ped/Pea-15 levels in the skeletal muscle and adipose tissues but not in the liver, accompanied by a chromatin reorganization assessed by Formaldehyde Assisted Isolation of Regulatory Elements (FAIRE) assays. Moreover, chromatin remodelling upon high fat diet does not result in nucleosome depletion but in changes in histone modifications. In particular, increased gene transcription well correlates with increased H4 acetylation and histone H3 dimethylation of lysine 4 on Ped/Pea-15 promoter, two active histone marks. In addition, a specific promoter region acquires typical features of enhancer elements such as monomethylated lysine 4 (H3K4me1) and acetylated lysine 27 (H3K27Ac) on histone H3 in the skeletal muscle tissue of HFD mice compared to STD mice. These two histone marks lack instead in the liver of both HFD and STD mice. These findings provide evidence for environmentally induced changes at Ped/Pea-15 promoter and, for the first time, highlight the presence of a distal, tissue-specific, regulatory element potentially involved in the upregulation of Ped/Pea-15 upon high fat diet administration. Since direct evidence linking specific environmental cues and metabolic disorders are still limited, addressing this issue will provide new insight into the molecular basis of type 2 diabetes as well as create novel translational perspective.