A systems-level computational analysis of the role of XIST in phenotypic plasticity in cancer

Faculty: Prof. Mohit Kumar Jolly (BE) and Prof. Srimonta Gayen (DBG)

XIST (X-inactive specific transcript) is a long noncoding RNA that drives X-chromosome inactivation (XCI) in female mammals. It can also govern epigenetic reprogramming and consequent cell-state transitions by recruiting many chromatin-modifying complexes. While the canonical role of XIST in dosage compensation is well-known, its role in determining the dynamics of chromatin remodelling and consequent patterns of phenotypic plasticity – the ability of cells to dynamically and reversibly alter their phenotype in response to environmental cues – remains poorly understood.

This project will focus on investigating the role of XIST in modulating phenotypic plasticity in cancer at a systems-level through analysis of multi-omics high-throughput data (RNA-seq, ATAC-seq, Hi-C at bulk and/or single-cell levels), and integrating that with developing mechanism-based deterministic or stochastic mathematical models to capture epigenetic remodelling driven cell-state transitions. Single-cell sequencing data will unravel the underlying patterns of cell-state variability, and mechanistic modelling will elucidate how the nonlinear emergent dynamics of regulatory networks shape the phenotypic plasticity landscape.

Identifying a role of XIST in phenotypic plasticity in cancer would expand current understanding of long noncoding RNAs in dynamic genome regulation and may reveal novel mechanisms underlying sex-specific disease progression patterns and clinical outcomes.

References:
https://elifesciences.org/articles/104191
https://www.pnas.org/doi/10.1073/pnas.2418096121
https://www.sciencedirect.com/science/article/pii/S0092867422005323