Research Domain

1. Mechanisms of functional chromatin organization: role of non-histone chromatin proteins, PC4 and HP1 (heterochromatin protein 1):
The research focuses on investigating the cooperative role of non-histone proteins PC4 and HP1α in maintaining Heterochromatin dynamics during neurogenesis and cognition. We are investigating the chromatin-mediated regulation of transcriptional fidelity, which is important for normal neuronal physiology. Using genetic knockdown mouse models and neural stem cell systems, we are investigating how the disruption of this axis affects neural development and animal behavior. This work aims to uncover chromatin-mediated mechanisms that safeguard neurogenic identity and resilience.

 2. Transcriptional regulation by histone chaperones NPM1 and NPM2: Implications in oral cancer:

3. The epigenetic landscape of oral cancer manifestation:
a) p300-mediated hyperacetylation regulated by NPM1 and p53; b) hyper arginine methylation by PRMT4:

DNA hypermethylation, histone modifications, and non-coding RNAs are the three major epigenetic mechanisms that predominantly contribute to cancer progression, along with driver mutation-driven cancer progression. Histones are hyperacetylated and hypermethylated in tumor tissues in oral cancer due to the over-expression of acetylated p300 and CARM1, important chromatin modifiers. Wild-type p53, mutant p53, NPM1, and GAPDH are also overexpressed in oral cancer, leading to increased autoacetylation of p300, thereby increasing its activity. 

Whole Exome Sequencing Analysis of 50 oral cancer women patients with tobacco chewing habit has revealed a few novel TP53 mutations and in the driver gene, CASP8. Double mutation in TP53 and CASP8 is associated with mortality and early relapse, along with poor pathological response. We are elucidating the role of these uncharacterized TP53 mutants, along with driver mutations, in the progression of oral carcinogenesis against the backdrop of histone hyperacetylation and p300. We are also targeting epigenetic modifiers with small-molecule inhibitors in conjunction with conventional chemotherapeutics to combat the progression of Oral cancer. 

 4. Histone Acylation and Lipid metabolism: Altered Lipogenesis in Liver and Brain in the context of Obesity:

Adipogenesis is the phenomenon where there is rampant metabolism that consequently accelerates metabolite-mediated epigenetic reprogramming. Mature adipocytes (fat cells) store excess energy by forming inert lipid droplets by adapting several metabolic pathways, including Fatty acid synthesis. During this process, intermediate metabolites like SCFAs (acetate, butyrate, crotonate, etc.) can be used by epigenetic enzymes to modify histones. A recent study from our lab has shown that p300-mediated histone lysine butyrylation increases during adipogenesis, and by probing them with a small molecule, LTK-14A, they were able to inhibit this modification and consequently adipogenesis without affecting the canonical acetylation reaction. Upon testing this molecule in different murine models, they found that LTK-14A can significantly curb obesity, liver steatosis and potentially liver fibrosis. We are also exploring the SCFA-mediated crosstalk between Liver and Brain in the context of rare histone acylation modifications.

5. Epigenetic regulation of neurogenesis: Role of p300/CBP-mediated acetylation in neurodevelopmental (autism), neurodegenerative disorders, and depression:

Epigenetic regulatory mechanisms, including DNA methylation, chromatin remodelling, histone modification, and microRNA expression, play critical roles in neurogenesis through spatiotemporal gene regulation. Any perturbation in these epigenetic modifications can contribute to neurodevelopmental and neurodegenerative disorders. As dysregulation of histone acetylation machinery is quite well established in the pathophysiology of some neurological disorders, we are looking at the p300/CBP mediated acetylation in neurodevelopmental (autism), neuropsychiatric (depression) and neurodegenerative (Parkinson's and Huntington's) conditions. By employing the p300/CBP KAT activity-specific activator, our group is looking at the effects on LTP deficit, memory and behavioural phenotypes and if it ameliorates the molecular and behavioural deficits in animal and cellular models. We also are looking gene expression levels impaired by the disease and subsequent KAT activator treatment.