Changes in expression of the various histone isoforms might play a role in cancer development and changes in cellular functions.
(Saikat Bhattacharya (Standing), Dr. Sanjay Gupta (Standing) and Ms. Divya Reddy)
The genome is the master blueprint of life- fortified by spool-like proteins known as Histones. Histones are present in many identical forms which are arranged in an octameric repeating structure around the genetic material-DNA and helps in packaging and arrangements of nearly seven feet long DNA in the microscopic cells. Scientists are trying to discover how changes in expression of the various histone isoforms might play a role in cancer development and changes in cellular functions.
The findings by researchers at the ACTREC-TMC, Mumbai – by Dr. Sanjay Gupta and his team members, provide novel insights into how different histone H2A isoforms, owing to slight alterations in amino acid substitution, dramatically bring about subtle differences in the stability of nucleosome. These differences alter gene expression and therefore phenotype.
These results were published in the journal “Epigenetics & Chromatin.”
“Liver being a visceral organ, its cancer is often difficult to treat. Hence, our lab has been working on identifying new candidate biomarkers and drug targets to tackle this disease. Our previous efforts led to the identification of the changes in the composition of a class of proteins known as histone isoforms. However, the molecular basis of how the highly similar isoforms contribute to disease development remained elusive. Hence, we decided to take up this challenge,” says Dr. Sanjay Gupta.
Researchers say the small differences in the amino acid composition of the histone isoforms makes it difficult to study them. “We used a holistic approach and collaboratively employed expertise in varied fields to address our questions,” added Dr. Gupta.
In this study, Dr. Gupta and his team members have shown that substitution of amino acids like Methionine (M51L) by Leucine and Lysine (K99R) by arginine alters the stability of histone-histone and histone–DNA complexes resulting in increased cell proliferation during cancer development.
“Our study in liver cancer suggests that although, the difference brought about by the isoforms is subtle, yet the epigenetic landscape of cells changes due to their sheer abundance in cells resulting in different gene expression pattern affecting the normal phenotype of the cell. The subtle nature of the epigenetic differences makes them more amenable to reversion and a potential target for future drug discoveries,” says Dr. Gupta about future perspectives of this study.
The multiple expertise’s to work out the intricacies of the project was provided by Integrated Biophysics and Structural Biology Group led by Dr. Kakoli Bose, in silico and bioinformatics experiments were carried out with support of Dr. Rajendra Joshi’s Bioinformatics Group at Centre for Development of Advanced Computing (C‑DAC), Pune and Mr. Nikhil Gadewal, BTIS, ACTREC.