July 2014 Researcher of the Month - Devi Thiagarajan, PhD
Diabetes is a multifactorial disease which is contributed by genetic and epigenetic changes. Aldose reductase, the key enzyme of the polyol pathway in the conversion of glucose to sorbitol has been implicated in the secondary complications of diabetes in animal models.
Our lab is interested in looking for the epigenetic changes induced by AR overexpression which might lead to the micro and macro vascular complications of diabetes. Recent studies in our laboratory have linked flux via AR to alterations in lipid homeostasis in ischemic and diabetic hearts. The purpose of my study is to focus upon the acetylation related changes upon hAR overexpression, specifically the class I HDACs.
Histone deacetylases (HDACs) are one of the major epigenetic modifiers which contribute to acetylation status of the proteins. The study focuses to delineate the mechanisms by which AR drives lipotocixity in hearts. Specifically, we probed if overexpression of hAR drives lipotoxicity via histone deacetylase-3 (HDAC3) dependent changes in regulators of fatty acids/lipid metabolism. Cardiomyocyte cells and hAR expressing mice hearts are used to address the mechanisms by which aldose reductase mediates lipotoxicity.
1. Vedantham S*, Thiagarajan D*, Ananthakrishnan R*, Lingjie W, Rosario R, Yu Shan Z, Goldberg I, Yan SF, Schmidt AM, Ramasamy R. Aldose Reductase drives hyperacetylation of Egr-1 in hyperglycemia and consequent upregulation of proinflammatory and prothrombotic signals. Diabetes. 2014. Feb; 63:761-774.*-authors contributed equally.
Commentary of this paper has also been published. Julia V. Busik and Maria B. Grant in the same journal: Diabetes 2014. Feb; 63:402-404.
2. Suri D, Veenit V, Sarkar A, Thiagarajan D, Kumar A, Nestler EJ, Galande S and Vaidya VA. Early stress evokes age-dependent biphasic changes in hippocampal neurogenesis, BDNF expression and cognition. Biol. Psychiatry. 2013. Apr; 73(7):658-66.
3. Thiagarajan D, Dev RR, Khosla S. The DNA methyltransferase Dnmt2 participates in RNA processing during cellular stress. Epigenetics. 2011. Jan;103-13.
4. Sowpati DT*, Thiagarajan D*, Sharma S, Sultana H, John R, Surani A, Mishra RK and Khosla S. An intronic DNA sequence within the mouse Neuronatin gene exhibits biochemical characteristics of an ICR and acts as a transcriptional activator in Drosophila. Mech. Dev. 2008,
Nov-Dec; 125(11-12):963-73. *-equal contribution
Thiagarajan D, Ananthakrishnan R, Schmidt AM and Ramasamy R. Reduced Hdac3 protein level in AR overexpression leads to lipotoxicity in mice. SHVM, Baltimore, USA. Sep 2013.
My future aim is to focus on the importance of Class II HDACs in diabetes associated cardiac complications and to delineate the mechanisms behind it.