Koustav SarkarSRM Institute of Science and Technology, India
Title: Epigenetic control of T-Helper (TH) cell differentiation during breast cancer is mediated by one of the Nucleotide Excision Repair (NER) pathway-associated proteins, Xeroderma Pigmentosum Complementation Group G (XPG)
Several proteins are involved in DNA repair mechanisms attempting to repair damages to the DNA continuously. One such protein is Xeroderma Pigmentosum Complementation Group G (XPG), a significant component in the Nucleotide Excision Repair (NER) pathway. TNF? and IFN-? secreted by CD4+T-Helper (TH) cells have antitumor activity followed by polarisation of TH1 phenotype in response to IL-12 secreted by dendritic cells, inducing expression of XPG which is downregulated in breast cancer. Therefore, we investigated the involvement of XPG in TH-cell differentiation in breast cancer. XPG knock-out (KO) PBMC and TH1 polarised CD4+ TH-cells isolated from breast cancer and control subjects blood samples were used to observe mRNA expressions of associated genes, % enrichment of corresponding epigenetic markers, and m6A RNA methylation levels to study the molecular mechanisms involved. Assays to investigate Cytotoxic T Lymphocyte (CTL) activity after cross checking extracellular secretion levels. Our XPGKO results indicated upregulation of TH2 and Treg, downregulation of TH1, and negligible change for TH17; reduced expression of genes associated with tumour suppression (TP53, BRCA1) and DNA repair (H2AFX, ATM) for breast cancer TH-cells. CTCF associated TH1 specific function, reduced %enrichment of XPG, CSA, and ERCC1, increased %enrichment of ?H2A.X, and altered histone modifications (methylation, deacetylation) at the IFN-? gene locus in XPGKO breast cancer TH1-cells. Increased m6A RNA methylation mediated by XPG leads to TH1 cell specificity, further inducing CTL activity by releasing extracellular IFG-?, which activates CD8+ CTLs. This article explores the association of the vital NER protein, XPG with the epigenetic modifications behind TH1 cell differentiation, augmenting the expressions of TH1-network genes to evoke protective immunity in breast cancer.
Dr. Koustav Sarkar has completed his PhD at the age of 28 years from Chittaranjan National Cancer Institute/Jadavpur University, Kolkata, India. Currently, he is the Research Assistant Professor in department of Biotechnology, SRM Institute of Science and Technology, Chennai, India. He presented papers in more than 50 national and international conferences. Dr. Sarkar has been involved in research over the last twenty years (including a Ph.D. and three Post-Docs) and made several important contributions to the development of advanced science and technology. He was involved in understanding the molecular mechanisms of the development of human immune responses in health & disease. Dr. Sarkar has already published 46 high-impact scientific publications in internationally reputed journals. He was also co-author of four book chapters. During PhD, Dr. Sarkar has developed a process for isolating glycoprotein(s) from neem leaf, which has immunomodulatory and cancer preventive functions. One patent (Patent Number: 259434; Grant Date: 12-Mar-2014) has been granted for this invention. He found out that the neem leaf glycoprotein helped to generate carcinoembryonic antigen specific anti-tumor immune responses utilizing macrophage & dendritic cell mediated antigen presentation to T and B cells and the induction of type 1 protective immunity. To study the intricate molecular mechanisms involved in the type 1 protective immunity, Dr. Sarkar moved to USA. Research from his US laboratory was essential in revealing for the first time a novel nuclear function for a well-known cytoskeleton structure associated protein, Wiskott Aldrich Syndrome Protein (WASp) in the transcriptional regulation of T helper cell 1 (Th1)-differentiation through its effect on epigenetic modifications at the T-BET gene-promoter locus. Since that time, Dr. Sarkar has been actively involved in further understanding how different types of epigenetic mechanisms are involved in T helper cell differentiation during breast cancer.