Allelic co-ordination of transcriptional bursting and heterogeneity in cancer

Faculty : Srimonta Gayen (MRDG), Mohit Kumar Jolly (BSSE)

Cancer is a highly dynamic and heterogeneous disease. Heterogeneity provides the flexibility to some cancer cells to become resistant to therapeutic treatment. Therefore, understanding heterogeneity in cancer in a quantitative manner is crucial. Recent years, heterogeneity in cancer have been studied extensively in terms of dynamic gene expression specially using single cell RNA-Sequencing but not at an allelic level. Recently we have shown that two alleles of a gene can act independently or in a coordinated fashion which leads to different level of gene expression noise. Therefore, to understand the source of heterogeneity in cancer more precisely, we need to explore coordination between alleles during the stochastic transcriptional bursting and related transcriptional noise. Therefore, a major goal of the proposal is to evaluate how the co-ordination between the two alleles of a gene leads to different level of heterogeneity during the course of the disease. We will explore genome wide allelic transcriptional burst kinetics through allele-specific single cell RNA-Sequencing analysis during different stages of disease progression in different type of cancer such as glioblastoma, leukemia etc. Finally, we will develop a mathematical model to assess the contribution coming from transcriptional burst and allelic co-operation in mediating cell-to-cell heterogeneity. Altogether, this study holds potential to facilitate the development of new therapeutic strategies for cancer.

Key references:

Naik HC, Hari K, Chandel D, Mandal S, Jolly MK, Gayen S (2021) Semi-coordinated allelic- bursting shape dynamic random monoallelic expression in pregastrulation embryos. iScience https://doi.org/10.1016/j.isci.2021.102954

Naik HC, Hari K, Chandel D, Jolly MK, Gayen S (2021) X upregulation is not global and extent of upregulation differs between ancestral and acquired X-linked genes. bioRxiv https://doi.org/10.1101/2021.07.18.452817

Lab websites:

Srimonta Gayen: https://srimontasd.wixsite.com/gayen-lab Mohit Kumar Jolly: https://be.iisc.ac.in/~mkjolly/