Transcriptome Analysis of Epigenetically Modulated Genome Indicates Signature Genes in Manifestation of Type 1 Diabetes and Its Prevention in NOD Mice

Classic genetic studies implicated several genes including immune response genes in the risk of developing type 1 diabetes in humans. However, recent evidence including discordant diabetes incidence among monozygotic twins suggested a role for epigenetics in disease manifestation. NOD mice spontaneously develop type 1 diabetes like humans and serve as an excellent model system to study the mechanisms of type 1 diabetes as well as the efficacy of maneuvers to manipulate the disease. Using this preclinical model, we have recently demonstrated that pharmacological inhibition of histone deacetylases can lead to histone hyperacetylation, selective up-regulation of interferon-γ and its transactivator Tbx21/Tbet, and amelioration of autoimmune diabetes. In the current study, we show that chromatin remodeling can render splenocytes incapable of transferring diabetes into immunodeficient NOD.scid mice. To elucidate the underlying mechanisms of drug-mediated protection against type 1 diabetes, we performed global gene expression profiling of splenocytes using high throughput microarray technology. This unbiased transcriptome analysis unraveled the exaggerated expression of a novel set of closely related inflammatory genes in splenocytes of acutely diabetic mice and their repression in mice cured of diabetes by chromatin remodeling. Analysis of gene expression by qRT-PCR using RNA derived from spleens and pancreata of cured mice validated the suppression of most of these genes, indicating an inverse correlation between the high levels of these inflammatory genes and protection against diabetes in NOD mice. In addition, higher-level expression of genes involved in insulin sensitivity, erythropoiesis, hemangioblast generation, and cellular redox control was evident in spleens of cured mice, indicating their possible contribution to protection against type 1 diabetes. Taken together, these results are consistent with the involvement of epistatic mechanisms in the manifestation of autoimmune diabetes and further indicate the utility of chromatin remodeling in curing this complex autoimmune disorder.