Molecular Mechanism of Transcriptional Regulation by Chromatin Reader Transcription Factor 19 (TCF19) during Metabolic Stress

Abstract

Changing nutritional environment confers epigenetic memories that often pre‐dispose the human body to certain metabolic disorders. Histone post‐translational modifications (PTMs), and their selective recognition by reader domain containing proteins constitute a transcription regulatory network that helps in maintaining cellular metabolic homeostasis, although the exact mechanism is still unclear. Here we have studied a novel glucose sensing and endoplasmic reticulum (ER) stress‐responsive transcription regulator, TCF19, which regulates transcription of key metabolic and stress‐responsive genes through recognition of histone PTMs. Through biochemical and biophysical techniques, we have found that TCF19 Plant Homeodomain (PHD) finger has a unique preference for the lysine 4 trimethylation of histone H3, which is a transcription activation modification. Using siRNA mediated TCF19 depletion in human hepatoma cell line HepG2 and primary human hepatocyte‐like cell HepaRG, we observed a global effect on metabolic pathways and interestingly the gluconeogenic genes were significantly upregulated. Through endogenous immunoprecipitation, we found that TCF19 interacts with components of a histone deacetylase complex NuRD (Nucleosome Remodelling and Deacetylase) and Chromatin immunoprecipitation studies indicate their co‐recruitment onto promoters of gluconeogenic genes under high glucose conditions, suggesting that the observed repression is possibly mediated in concert with NuRD complex. In‐depth analysis revealed that TCF19 also represses gluconeogenesis in response to insulin stimulation in both HepG2 and HepaRG cells. Deletion mutants of TCF19 lacking the PHD finger were unable to repress gluconeogenesis in response to insulin, underscoring the importance of histone modification mediated regulation of insulin action. We have also observed that TCF19 associates with several other transcription regulators of metabolic genes which have an important role in ER stress and cell survival and has been widely linked to type 2 diabetes progression. Overall, our study presents a novel transcription regulator that integrates metabolic (glucose), as well as hormonal (insulin) signal. These findings seek to expand our understanding of the role of epigenetic changes in metabolic regulation, and in the long run, provide an opportunity for therapeutic intervention to treat metabolic disorders like diabetes.Support or Funding InformationThe study was supported by research grant entitled Biomolecular Assembly, Recognition and Dynamics (BARD) (Grant 12‐R&D‐SIN‐5.04‐0103) by the Department of Atomic Energy (DAE), Govt. of IndiaThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.