Epigenetics, Cancer biology, Onco-histone mutation, DNA Damage Response, Immunotherapy, Host-parasite interaction, Leishmaniasis
Summary of Research:
According to global cancer statistics 2020, the global cancer burden is expected to rise 47% from 2020 to 2040. Due to changing socio-economic scenario and sedentary lifestyle, the Indian cancer burden is also on the rise, therefore an urgent research investment in the cancer field is the need for better-personalized drug development. Tumorigenesis is an evolving multistep process involving genetic and epigenetic changes that provide a growth advantage to cancer cells over normal cells. The next-generation genome sequencing of cancer cells has identified new recurrent mutations, but the exact biological effects of those mutations are unknown. Our laboratory primarily applies biochemistry, molecular cell biology, genetic and epigenetic approaches to study such mutations in proteins and DNA-protein complexes. Nucleosome remodelers, chromatin modifiers(writers, erasers), and readers of histone and DNA modifications are frequently altered in cancer. However, the oncogenic nature and mechanisms of histone mutations itself in cancer are not clear. Histones are not only the packaging material of eukaryotic DNA but also control the dynamic nature of chromatin, essential for replication, transcription, and DNA repair. We are applying the diverse techniques to study the following topics:
1. The role of “Readers” and “Erasers” proteins in the DNA Damage Response (DDR) pathway
We are focusing on demethylases and bromodomain proteins, to identify novel synthetic lethal genetic interactions of “readers/writers “protein with DDR pathway genes.
2. Understanding the oncogenic and biological effect of cancer-associated histone H3 and H4 mutations
Very high-frequency somatic heterozygous missense mutations in histone H3 genes at highly conserved amino terminus residues (K27, K36 and G34) were reported in pediatric high-grade gliomas, sarcomas, head-neck cancers, and carcinosarcomas as well as many adult cancers. H3.3K27M oncohistone reduces repressive histone modification marks, H3K27 trimethylation in trans by altering activities of polycomb repressive complex 2, thus interfering with the developmentally regulated genes whereas H3.3G34R mutation reduces activating mark, H3K36me3 in cis. These mechanisms suggest alteration in gene expression pattern and may contribute toward tumorigenesis. On the other hand, few studies argue that tumorigenesis may likely occur due to genomic instability caused by H3.3K27M and H3.3G34R oncohistones. How differential PTMs of H3K36 and H3K27 may impact genome stability is not clear. Also, the common mechanism of oncohistone mutants (H3.3K27M and H3.3G34R) toward genome instability is elusive.
3. Identifying functions of histone demethylases to enhance the antitumor potential of chimeric antigen receptor (CAR) T cell
CAR T cell therapy is successful in hematological cancers but its potential for solid tumors needs further extensive research. Therefore, our lab has a growing interest in combination therapy to improve tumor resistance against CAR T cells.
Ramalingaswami Re-entry Fellowship, Department of Biotechnology, Government of India (2017-2018)