Lymphocytes from Patients with Type 1 diabetes Display a Distinct Profile of Chromatin Histone H3 Lysine 9 Dimethylation: An Epigenetic Study in Diabetes

Abstract

OBJECTIVE: The complexity of interactions between genes and the environment is a major challenge for Type I diabetes (T1D) studies. Nuclear chromatin is the interface between genetics and environment, and the principal carrier of epigenetic information. Since histone tail modifications in chromatin are linked to gene transcription, we hypothesized that histone methylation patterns in cells from T1D patients can provide novel epigenetic insights into T1D and its complications.

RESEARCH DESIGN AND METHODS: We used Chromatin immunoprecipitation linked to microarray (ChIP-chip) approach to compare genome-wide histone H3 lysine 9 dimethylation (H3K9me2) patterns in blood lymphocytes and monocytes from T1D patients versus healthy control subjects. Bioinformatics evaluation of methylated candidates was performed by Ingenuity Pathway Analysis (IPA) tools.

RESULTS: A subset of genes in the T1D cohort showed significant increase in H3K9me2 in lymphocytes, but not monocytes. CLTA4, a T1D susceptibility gene, was one of the candidates displaying increased promoter H3K9me2 in T1D. IPA identified two high scoring networks that encompassed genes showing altered H3K9me2. Many of them were associated with autoimmune and inflammation-related pathways such as TGF-β, NF-κB, p38MARK, TLR and IL6. IPA also revealed biological relationships between these networks and known T1D candidate genes.

CONCLUSIONS: The concerted and synergistic alteration of histone methylation within the identified network in lymphocytes might have an effect on the etiology of T1D and its complications. These studies provide evidence of a novel association between T1D and altered histone methylation of key genes that are components of T1D related biological pathways and also a new understanding of the pathology of T1D.