Abstract
Epigenetic alteration of the genome has been shown to provide palliative effects in mouse models of certain human autoimmune diseases. We have investigated whether chromatin remodeling could provide protection against autoimmune diabetes in NOD mice. Treatment of female mice during the transition from prediabetic to diabetic stage (18-24 weeks of age) with the well-characterized histone deacetylase inhibitor, trichostatin A effectively reduced the incidence of diabetes. However, similar treatment of overtly diabetic mice during the same time period failed to reverse the disease. Protection against diabetes was accompanied by histone hyperacetylation in pancreas and spleen, enhanced frequency of CD4(+) CD62L(+) cells in the spleen, reduction in cellular infiltration of islets, restoration of normoglycemia and glucose-induced insulin release by beta cells. Activation of splenic T lymphocytes derived from protected mice in vitro with pharmacological agents that bypass the antigen receptor or immobilized anti-CD3 antibody resulted in enhanced expression of Ifng mRNA and protein without altering the expression of Il4, Il17, Il18, Inos and Tnfa genes nor the secretion of IL-2, IL-4, IL-17 and TNF-α proteins. Consistently, expression of the transcription factor involved in Ifng transcription, Tbet/Tbx21 but not Gata3 and Rorgt, respectively, required for the transcription of Il4 and Il17, was upregulated in activated splenocytes of protected mice. These results indicate that chromatin remodeling can lead to amelioration of diabetes by using multiple mechanisms including differential gene transcription. Thus, epigenetic modulation could be a novel therapeutic approach to block the transition from benign to frank diabetes.
Highlights
Epigenetics, heritable changes in gene expression without altering the DNA sequence, involves DNA methylation and chromatin remodeling by phosphorylation, methylation, sumoylation, ubiquitination, and acetylation of histones[1]
Protection was exerted by Trichostatin A (TSA) since administration of the vehicle, dimethyl sulfoxide (DMSO) failed to provide similar palliative effect
Our data demonstrate that treatment with the well-characterized histone deacetylases (HDAC) inhibitor TSA can attenuate spontaneous autoimmune diabetes in female NOD mice
Summary
Epigenetics, heritable changes in gene expression without altering the DNA sequence, involves DNA methylation and chromatin remodeling by phosphorylation, methylation, sumoylation, ubiquitination, and acetylation of histones[1]. Hyperacetylated histones are correlated with transcriptional permissiveness whereas hypoacetylated histones mediate gene repression[1]. Small molecule HDAC inhibitors are major tools for studying the correlation between overall chromatin modifications and cellular functions[2]. The HDAC inhibitors are often used to inhibit the HDAC activity. Inhibition of HDAC activity in vitro increases histone acetylation within 2-4 h of treatment with HDAC inhibitors including Trichostatin A (TSA), and induces up- and down-regulation of genes[3,4]. The HDAC inhibitor mediated regulation of a small portion of genes (5-20%) is dependent on the cell type, dose and type of inhibitors used, suggesting that chromatin remodelling by HDAC inhibitors is a gene-specific event with a variable transcriptional outcome[2,3,4]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
