Dr. Deepash Kothiwal’s interview with Bio Patrika hosting “Vigyan Patrika”, a series of author interviews. Dr. Kothiwal completed his PhD with Prof. Shikha Laloraya at the Dept. of Biochemistry, Indian Institute of Science Bangalore, India. The main focus of his doctoral study was to investigate the role of cohesin in subtelomeric silencing and organization. Currently he is a postdoctoral research fellow in the lab of Dr. Stephen Buratowski at the Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, USA. His research interest include regulation of gene expression. Deepash published his PhD research findings as first author in two articles: “A SIR-independent role for cohesin in subtelomeric silencing and organization” published in Proceedings of the National Academy of Sciences of the United States of America (2019) and “Cohesin dysfunction results in cell wall defects in budding yeast” published in Genetics (2020).
How would you explain your paper’s key results to the non-scientific community?
Genetic information is stored in chromosomes inside the cells; and for organisms to survive, this information must be accurately passed on through the generations. Cohesin is a protein complex involved in chromosome segregation and is critical for genome stability.
The ends of chromosomes are called telomeres. Genes present near telomeres are expressed at a lower level and changes in their expression level can lead to multiple diseases in humans, including muscular dystrophy. Our work in S.cerevisiae, a model organism, reveals a novel role of Cohesin in the regulation of gene expression at telomeres. We find that cohesin regulates gene expression by maintaining the chromatin structure, independent of its role in chromosome segregation. Furthermore, our work also shows that cohesin plays an important role in the maintenance of cell wall, the protective layer around yeast cells, by regulating the expression of cell wall related genes. Taken together, we have uncovered new, unanticipated functions of the cohesin complex and have shown how mutations can affect these functions and possibly lead to disease condition.
What are the possible consequences of these findings for your research area?
Our study has contributed towards solving a long-standing puzzle about factors involved in the repression of the subtelomeric region, not overlapping with SIR-binding. In S.cerevisiae, telomeres exist in a heterochromatin-like structure and transcription within ~20 kb from telomeres is repressed, partly by the histone modifying SIR-complex, a phenomenon known as telomere position effect (TPE). Interestingly, extensive subtelomeric repressed domain lies outside the SIR-binding region, but the mechanism of silencing in this region was poorly understood. We have found that cohesin is required for the repression of subtelomeric genes; and importantly, this repression is independent of Sir proteins. This observation opens new avenues in the field, and it would be really interesting to study whether other factors involved in chromatin structure maintenance would also be required for this Sir-independent silencing.
The second part of our study reveals a function of cohesin in cell wall maintenance. Although a role for cohesin in cell wall integrity was suggested earlier, many questions remained unanswered. Our work shows that cohesin regulates expression of many genes involved in cell wall biogenesis and organization. Furthermore, we also show that cohesin’s role in the regulation of gene expression is independent of its role in genome segregation. This is important since a mutation in cohesin that causes failure in genome segregation can lead to cancer or cell death. In contrast deregulated gene expression leads to developmental defects, collectively known as cohesinopathies. Therefore, our study also hints at the possible changes in gene expression that could lead to cohesinopathies.
What was the exciting moment (eureka moment) during your research?
Eureka moment for me was the result that identified cohesin as the first factor involved in the repression of subtelomeric region, not overlapping with SIR-binding. We were also excited to see that the effects on gene expression were independent of cohesion (genome segregation), since it has been really difficult in the field to segregate the role of cohesin in sister chromatid cohesion i.e. genome segregation from its other functions.
What do you hope to do next?
During my doctoral research, I developed a keen interest in the regulation of gene expression. Gene expression can be regulated by multiple mechanisms and at multiple levels, including chromatin organization, transcription initiation, elongation, and termination. Dr. Steve Buratowski’s group at Harvard medical School was one of the first group to show the role of RNA pol II CTD phosphorylation in the regulation of transcription. I recently joined his group where I am trying to understand CTD phosphorylation code that drives transcription from initiation to termination.
Where do you seek scientific inspiration?
I get scientific inspiration from people around me. I have been lucky to be surrounded by astute scientific minds both during my PhD and now in my post-doc. My PhD advisor Dr. Shikha Laloraya constantly motivated me and guided me to do productive research. Similarly, my postdoctoral advisor Dr. Steve Buratowski has a unique ability to solve complicated problems and always strives for excellence. His amicable mentorship creates a great environment to carry out research. I also draw inspiration from scientific history that shows us how scientists worked against all odds and created a world where new ideas are met with excitement rather than skepticism.
How do you intend to help Indian science improve?
Quality of science in India has been improving every year and we already have a pool of great scientists. On my part, I hope to do good research and hopefully being an Indian that would inspire fellow citizens. Given an opportunity, I would love to do research in India and work towards improving scientific culture further. I believe that we need to invest more at the school level to inculcate scientific aptitude at a very
young age. It can create a generation of science enthusiast and that could help Indian science enormously.
Deepash Kothiwal, Shikha Laloraya. A SIR-independent role for cohesin in subtelomeric silencing and organization. Proceedings of the National Academy of Sciences of the United States of America (2019). 116(12):5659-5664.
Deepash Kothiwal, Swagathnath Gopinath, Shikha Laloraya. Cohesin dysfunction results in cell wall defects in budding yeast. Genetics, iyaa023 (2020).
Read more about Prof. Shikha Laloraya lab here: https://biochem.iisc.ac.in/shikha-laloraya.php