Dr. Kothiwal completed his PhD with Prof. Shikha Laloraya at the Department 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 interests include regulation of gene expression.
Deepash published his PhD research findings as first author in two articles:
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A SIR-independent role for cohesin in subtelomeric silencing and organization published in PNAS (2019)
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Cohesin dysfunction results in cell wall defects in budding yeast published in Genetics (2020)
Author Interview
How would you explain your paper’s key results to the non-scientific community?
Genetic information is stored in chromosomes inside cells; for organisms to survive, this information must be accurately passed on through generations. Cohesin is a protein complex involved in chromosome segregation and is critical for genome stability.
The ends of chromosomes are called telomeres. Genes near telomeres are usually expressed at lower levels, and changes in their expression can lead to diseases in humans, including muscular dystrophy. Our work in S. cerevisiae, a model organism, reveals a novel role of cohesin in regulating gene expression at telomeres. We found that cohesin regulates gene expression by maintaining chromatin structure, independent of its role in chromosome segregation.
Furthermore, we found that cohesin also plays a role in maintaining the cell wall—the protective layer around yeast cells—by regulating the expression of cell wall-related genes. Altogether, we uncovered new, unexpected functions of the cohesin complex and showed how mutations can impact these roles, possibly leading to disease conditions.
What are the possible consequences of these findings for your research area?
Our study contributed to solving a long-standing puzzle regarding factors involved in repression of subtelomeric regions not overlapping with SIR-binding. In S. cerevisiae, telomeres are organized in heterochromatin-like structures, and transcription within ~20 kb of telomeres is repressed, partly by the SIR-complex. However, many repressed regions lie outside SIR-binding zones, and the mechanism behind this was poorly understood.
We found that cohesin is required for repression of these subtelomeric genes—and this repression is independent of Sir proteins. This opens new avenues in understanding chromatin-based silencing and raises the question of whether other chromatin structure regulators may also be involved in SIR-independent silencing.
The second part of our study shows a role of cohesin in cell wall maintenance. Although this was hinted at in past studies, many questions were unresolved. Our work demonstrates that cohesin regulates the expression of many genes involved in cell wall biogenesis and structure. Importantly, this role in gene regulation is independent of cohesin’s well-known function in genome segregation.
Mutations in cohesin that affect genome segregation can cause cancer or cell death. In contrast, its gene regulatory defects can cause developmental disorders collectively termed cohesinopathies. Our findings provide insights into how gene expression changes may contribute to such disorders.
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?
The eureka moment came when we identified cohesin as the first known factor involved in repression of subtelomeric regions not overlapping with SIR-binding. We were also excited to see that the gene expression effects were independent of cohesion (genome segregation). It has been a major challenge in the field to distinguish cohesin’s role in sister chromatid cohesion from its other functions.
What do you hope to do next?
During my PhD, I developed a keen interest in understanding gene expression regulation. This can occur at multiple levels, including chromatin organization, transcription initiation, elongation, and termination.
Dr. Steve Buratowski’s group at Harvard Medical School was among the first to show the role of RNA Polymerase II CTD phosphorylation in regulating transcription. I have recently joined his lab to investigate the CTD phosphorylation code that governs the transcription cycle from initiation to termination.
Where do you seek scientific inspiration?
I draw scientific inspiration from the people around me. I’ve been fortunate to work with brilliant minds during both my PhD and postdoc. My PhD advisor, Dr. Shikha Laloraya, always motivated and guided me toward productive research. Similarly, my postdoc mentor, Dr. Steve Buratowski, is exceptional at solving complex problems and fosters a great environment for research.
I also find inspiration in scientific history—seeing how scientists pursued knowledge against the odds and helped create a world where new ideas are welcomed with excitement rather than skepticism.
How do you intend to help Indian science improve?
Science in India has been advancing rapidly, and we already have a strong base of talented scientists. Personally, I hope to contribute through high-quality research and, as an Indian, inspire others in the process.
If given the opportunity, I would love to return and conduct research in India, further strengthening its scientific culture. I also believe we need to invest more in science education at the school level, to nurture curiosity and scientific thinking early. A generation of science enthusiasts could greatly benefit Indian science in the long run.
References
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Deepash Kothiwal, Shikha Laloraya. A SIR-independent role for cohesin in subtelomeric silencing and organization. PNAS (2019). 116(12):5659-5664. Link
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Deepash Kothiwal, Swagathnath Gopinath, Shikha Laloraya. Cohesin dysfunction results in cell wall defects in budding yeast. Genetics, iyaa023 (2020). Link
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