Fine Tuning Gene Expression in Physiology and Pathophysiology: Implications in Therapeutics

Abstract: 
The highly ordered nucleoprotein structure in the eukaryotic nuclei is referred as chromatin. Though DNA sequence is the template for gene expression, the fine tuning of this process is mediated by the epigenetic machinery. Broadly, epigenetics refers to the modification of DNA, and the proteins that help organize the eukaryotic DNA. The protein component of chromatin undergoes several reversible post-translational modifications such as acetylation, methylation, phosphorylation etc., which occur on specific amino acid residues. We have found that lysine acetylation and arginine methylation of histones are essential for regulating the synthesis of mRNA as well as microRNA with functional consequences. The acetylation of proteins assisting transcription activation has also been found to be essential for the activation of gene expression. 

In pathophysiological conditions such as cancer, AIDS and in neurodegenerative disorders, homeostasis is affected, and the state of these modifications also undergoes alteration. Hence, enzymes responsible for these modifications could be target for new generation epigenetic therapeutics. We have discovered a few small molecules which specifically target these enzymes and eventually suppress tumor growth, viral multiplication in AIDS and enhance cognate brain function in a model of neurodegeneration.  Besides therapeutic implications, these efforts significantly contribute to our understanding of fundamental disease biology.