Research Projects

Amino acids alter several cellular processes through its metabolism and signaling. Our recent finding in Saccharomyces cerevisiae suggests that supplementing methionine induces proliferation and we identified the role of a transcription factor Gcn4’ role in regulating this growth response. During this study, we observed that several methyltransferases are differentially expressed in Gcn4 dependent manner in methionine supplemented conditions. Specifically, we observed significant down regulation of key phospholipid methyltransferases in the cells lacking Gcn4. As phospholipids are the predominant acceptors of methyl pools, when this phospholipid methylation is blocked, it may lead to several epigenetic changes in the cell. Here, we will address the role of amino acid response regulator Gcn4’ in regulating the epigenetic status of the cell. On the other hand, our preliminary data exploring the role of Gcn4 in aging shows Gcn4 deletion increases the chronological lifespan of S. cerevisiae. Integrating these two observations, we hypothesised that Gcn4 dependent epigenetic regulation of cells could play a role in determining the lifespan. Further, as Gcn4 is a conserved transcription factor in other organisms, we will explore the conservation of these processes in other model systems such as C. elegans. Understanding this mechanism in methionine dependent conditions let us to understand how global epigenetic pattern is regulated in the cancer cells that are known to uptake more methionine and known to have higher expression of Gcn4 homologue ATF4 during proliferation. In this proposed study, using multidisciplinary approaches such as genomics, metabolomics, and biochemical approaches, we will address how amino acid response regulator Gcn4 play a role in altering the methylation status histones, DNA, RNA, and proteins. Further, we will investigate how these regulatory mechanisms impacts the gene expression of aging related processes and its downstream role in cellular and organismal aging using Saccharomyces cerevisiae and C. elegans as a model system. Overall, this work will have a huge impact on understanding how dietary supplementation of amino acids and phospholipids signals in different cellular processes, specifically epigenetic status of the cell by coordinating methylation of different molecules. My specific aims in this context are as follows. 1. To investigate the role of amino acid response regulator Gcn4 in altering the epigenetic status of the cell. 2. To elucidate the role of Gcn4 dependent altered epigenetic landscape on transcriptional reprogramming. 3. Understanding the importance of balanced methylation circuits between molecules on cellular aging. 4. To validate the conservation of Gcn4 homologue ATF4’s role in regulating epigenetic status of different molecules and lifespan in C. elegans