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Discovery of a new Nonhistone Chromatin Organizer
Multifunctional nonhistone chromatin protein PC4 is critical for genome Organization, autophagy regulation, B cell differentiation, adult neurogenesis, and Memory extinction.
Histone-interacting non-histone chromatin proteins are critical to fine-tuning genome organization and function. The TDL has discovered a non-canonical role of human transcription coactivator PC4 as a non-histone chromatin protein involved in genome compaction and, consequently, having a crucial role in the regulation of autophagy, DNA repair, B-cell differentiation, neurogenesis, memory extinction, and potentiation of p53 function.
The p53 regulates epigenetic enzymes: implications in oral cancer and adipogenesis
p53 regulates epigenetic enzymes.
The chromatin protein PC4 was found to be a p53-responsive gene, and PC4 is an activator of the p53 function. It also regulates selected mutant p53-mediated gene regulation. This is the first reported p53 positive regulatory loop that we identified.
We found that wild-type p53 and a few selected p53 mutants induce the autoacetylation of KAT3B, implicating the role of p53 in the maintenance of epigenetic landscape, which could be exploited in oral cancer, as revealed by us from our analysis of a large number of patient samples. p53-mediated inhibition of PRMT4/CARM1 expression also alters histone arginine methylation patterns and inhibits adipogenesis.
A nucleolar protein activates RNA polymerase II driven transcription: implications in oral cancer
Nucleolar protein NPM1, a histone chaperone, induces p300-autoacetylation and activates RNA polymerase II-driven transcription, thereby oncogenesis.
The nucleolar protein NPM1 was established as a histone chaperone and a key regulator of RNA polymerase II-driven transcription upon acetylation by KAT3B/p300. We found that NPM1 is another inducer of p300 autoacetylation and thus plays a crucial role in the manifestation of oral cancer. NPM1 and acetylated NPM1 are being exploited as diagnostic markers and therapeutic targets.
Epigenetic landscape of oral cancer
A schematic to explain probable mechanisms of co-operative action between YY1 and CARM1 to either suppress or promote carcinogenesis by upregulating either YY1 responsive tumor suppressor genes (such as BRCA1, p53 and p73) or YY1 responsive oncogenes (such as c-Myc, c-Fos and Erb B2) respectively.
(Fig. Ref.: Behera AK et al., Oncotarget, 2019)
Our analysis of patient samples established that hyperacetylation and arginine methylation are the general epigenetic landscape of oral cancer. Mechanistically, so far, we have unraveled the induction of KAT3B autoacetylation by p53, NPM1, and GAPDH, and the overexpression of CARM1/PRMT4 caused by YY1 could be causally related to hyperacetylation and hyper arginine methylation respectively in oral cancer.
Small molecule modulators of epigenetic enzymes
A) Small molecule modulators of chromatin modifying enzymes to elucidate differentiation pathways:
Differential expression of various genes involved in muscle differentiation as probed by PCAF-specific inhibitor Embelin (Fig. Ref.: Modak R et al., ACS Chem Biol., 2013).
Using natural compounds as synthons, we have synthesized several small molecule modulators of epigenetic enzymes, especially lysine acetyltransferases, PRMT4 (arginine methyltransferase), and aurora kinase. These modulators have been used to elucidate the epigenetic regulation of different differentiation pathways: neurogenesis, adipogenesis, and myogenesis. Furthermore, a few of them show excellent potential to be epidrugs: activator of p300/CBP for spinal cord injury repair and LTK14A, an inhibitor of histone butyrylation for obesity/NASH treatment. Many of these modulators are being used as research reagents worldwide.
PRMT4/CARM1 selective inhibitor TBBD (ellagic acid). The docked conformation of TBBD near the KAPRK motif of histone H3 on the CARM1 active site. (Fig. Ref.: Selvi RB et al., J Biol Chem, 2010)
Elucidation of glial differentiation pathway using small molecule inhibitor of PRMT4. (Fig. Ref.: Selvi BR et al., Mol Biol Cell, 2015)
Specific KAT activator to promote Neurogenesis
CSP-TTK21 mediated p300 autoacetylation and its effects in neurogenesis (Source: Smitha AS et al., ACS Chem Biol., 2024).
B) Inhibitors of KATs: potential therapeutic molecules
Implications of KAT inhibitors as the antineoplastic therapeutics (Fig. Ref.: Arif et al., Chem Biol., 2010)
C) Specific KAT activator: Implications in Neurological Disorders:
Activation of p300/CBP by specific small molecule activator-induced neurogenesis and memory formation.
D) Butyrylation meets adipogenesis - probed by p300 catalyzed acylation-specific small molecule inhibitor: Implication in anti-obesity therapy
Selective inhibition of p300 catalysed histone butyrylation by LTK-14A without affecting its canonical acetyltransferase activity leads to inhibition of adipogenesis and attenuation of obesity.
Surface-Enhanced Raman Scattering (SERS): A Tool to Screen and Characterize Small Molecule Modulators of Enzymes
SERS study of specific binding of felodipine to Aurora A (Fig. Ref.: Karthigeyan et al., Proc Natl Acad Sci U S A, 2014)
The interdisciplinary environment of our centre encouraged us to explore novel methods to understand biomolecular (enzyme) dynamics upon interacting with small molecule modulators. We have established surface-enhanced Raman spectroscopy (SERS) as a tool to screen and characterize small molecule modulators, which could be highly useful for future drug discovery programs.
CMT (Centre for Marine Therapeutics)
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