Equational qualification:
Ph.D. Molecular Biology,
M.Sc. Microbiology,
B.Sc. Microbiology
Positions held (including current)
i. Ramalingaswami Fellow,a DBT funded programme for independent research.UM-DAE CEBS (India, 2013 – current).
ii. Research FellowLaboratory of Tumour Biology, Dr. Stephen Baylin,Johns Hopkins Med. Inst. (JHU, USA: 2007- 2013).
iii. Visiting FellowLaboratory of Cell and Molecular Biology, Dr. Carl Wu.National Cancer Inst., (NIH USA: 2002-2007).
iv. Research Scholar and Post-doctoral Fellow.Tata Institute of Fundamental Research. (India,1996-2002).
Research Areas
https://www.researchgate.net/profile/Subhojit_Sen/projects
A. Developing Chlamydomonas reinhardtii as a model system to study stress induced epigenetic and genetic changes.
Goal: Chlamydomonas, is a single celled green algae popularly nicknamed as the "green yeast" mimicking the haploid-diploid life cycle of the budding yeast. Having diversified from both animals and plants about a billion years ago, Chlamy forms an excellent link to study evolutionary conserved epigenetic mechanisms in eukaryotes. We are developing basic phenotypic assays to track epigenetic changes in Chlamydomonas via gene expression, along with generating quick novel molecular tools to assay both candidate genes as well as genome wide profiles of epigenomic changes due to stress. These assays will enable us to develop Chlamydomonas as a high-throughput discovery tool for novel epigenetically active compounds from traditional medicine. We hope to exploit the mitotic as well as meiotic cycles of this model organism to address molecular basis of transgenerational inheritance in nuclear genomes and how that might affect/influence/interact with organellar genomes. Lastly, being at the cusp of being unicellular versus multicellularity (its close cousin Volvox), we aim to understand the stress induced epigenetic mechanisms that pushes cells to shuttle between these two phenotypes. The eventual aim is to discover the common principles of multicellularity. This will not only have basic implications in understanding developmental biology, but also how cancer cells break these multicellular rules to metastasize as unicellular entities and re-establish a multicellular tumour at a distant site.
B. Understanding stress induced aberrant epigenetic memories in stem cells that eventually predispose us to non-communicable diseases like cancer.
Goal: Studies on epigenetic origins of cancer have revealed molecular underpinnings of a developmental program gone awry. Using environmentally induced oxidative stress as a model we demonstrated how early epigenetic changes directed towards CpG rich containing chromatin can serve as a memory mechanism to shut down tumour suppressor genes. It has also been shown by Easwaran H et. al., how bivalent chromatin in stem cells serve as an additional module for such targeted events. Connecting the dots, this project (in collaboration with Johns Hopkins) delves into developing sequential ChIP to generate the first combinatorial map of histone modifications at the mononucleosome level, hoping to dissect this problem further. Bivalent chromatin consists of doubly marked active as well as repressive histone modifications, namely H3K4me3 and H3K27me3, both on the same mononucleosome. By expanding a modified sequential ChIP approach on highly purified mononucleosome substrates to genome wide approaches of massively parallel sequencing, we hope to understand its links with CpG islands, their DNA methylation and H2A.Z status. Our analysis revealed that both marks co-exist on the same nucleosome but never on the same histone peptide. Further, genome wide analysis enabled us to understand how bivalent chromatin could serve as a connecting link between “stemness” and a cancer specific epigenome. Our hypothesis is to understand the molecular basis of stress induced epigenetic memories that can predispose you to or prevent you from going down the cancer cascade. We aim to develop temporally separated cell line models that help us address these queries.
C. Developing new models towards curricular research
Goal: Having being involved with multiple education platforms, we have realised the void of bona fide model systems that can be used in simple laboratory set-ups in India, particularly in challenging rural contexts. In that regards, we are trying to develop diverse models that are validated by hard science in the laboratory, but can be a useful tool not only to learn scientific methods in Biology, but also enable the citizen scientist at home to ask curiosity driven questions.
Some examples of problems we have been addressing are:
1) Becoming a microbiologist at home - test the efficacy of antibiotics
2) Estimate the nutrition potential of grains you consume at home.
3) Developing the water-flea as a simple model to understand stress induced gene expression.
D. Science, Society and Sexuality
Goal: Having worked within four walls of a lab for way too long, many STEM scientists are dissociated from the reality of connecting with the larger ecosystem of common knowledge and disseminating the process of science and scientific temper. In today's age of Social Media polarization, it is the responsibility of scientists to step out of their cocoon and engage with the public on larger discussions pertaining to science versus dogmatic beliefs. We need to collectively understand and differentiate - what is scientific. One major area of focus under this umbrella will be understanding the behavioural aspects of sex, gender and sexuality. As we progress further, it is essential for us to understand what makes us different, appreciate the need for that diversity and create inclusive scientific platforms that can have a place for everyone on board, irrespective of your origin, caste, gender, orientation etc. The final aim of this project is to continue the broader conversation with society on various aspects of science: breaking the constructs of normal versus the 'abnormal'.
Selected publications
(Full List - http://scholar.google.co.in/citations?user=uPa54XcAAAAJ&hl=en)
i. Hindsight is 2020: Science Funding Versus Focus in the COVID-era. S Sen, Confluence, Indian Academy of Sciences, 2020.
ii. A Novel Method to Generate MNase Ladders Reveal Rapid Chromatin Remodeling upon Gametogenesis and Mating in Chlamydomonas. P Potdar, P Pinto, N D’Souza, P Joshi, A Malwade, S Sen, Protist 169 (5), 632-644, 2018.
iii. Generating Nucleosomal Ladders In Vivo by Releasing Endogenous Endonucleases in Chlamydomonas reinhardtii. N D’Souza, P Joshi, S Kaginkar, S Sen, Plant Mol. Biol. Rep. 36, 363–371 2018.
iv. DNA methylation patterns separate senescence from transformation potential and indicate cancer risk. Xie, et al Cancer Cell 12;33(2):309-321. e5.doi:10.1016/j.ccell.2018.01.008.2018
v. Genome-wide positioning of bivalent mononucleosomes. S Sen, KF Block, A Pasini, SB Baylin, H Easwaran, BMC medical genomics Sep 15;9(1):60. doi: 10.1186/s12920-016-0221-6,2016
vi. Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb members to promoter CpG Islands
HM O'Hagan, W Wang, S Sen, et al Cancer Cell 20 (5), 606-619, 2011.
vii. Aberrant silencing of cancer-related genes by CpG hypermethylation occurs independently of their spatial organization in the nucleus
HP Easwaran, L Van Neste, L Cope, S Sen, HP Mohammad, GJ Pageau, JB Lawrence, JG Herman, KE Schuebel and SB Baylin Cancer Research 70 (20), 8015-8024, 2010.
viii. Chz1, a nuclear chaperone for histone H2AZ
E Luk, ND Vu, K Patteson, G Mizuguchi, WH Wu, A Ranjan, J Backus, S Sen, M Lewis, Y Bai, C Wu. Molecular Cell 25 (3), 357-368, 2007.
ix. Swc2 is a widely conserved H2AZ-binding module essential for ATP-dependent histone exchange. WH Wu, S Alami, E Luk, CH Wu, S Sen, G Mizuguchi, D Wei, C Wu Nature Structural & Molecular Biology 12 (12), 1064-1071,2005
x. ATP-driven exchange of histone H2AZ variant catalyzed by SWR1 chromatin remodeling complex. G Mizuguchi, X Shen, J Landry, WH Wu, S Sen, C Wu Science 303 (5656), 343-348,2004