Highlights

PhD Institution: National Centre for Biological Science, India Post PhD Institution: Max Planck Institute of Molecular Cell Biology and Genetics, Germany

Research

Research theme

Many RNA and RNA binding proteins form dynamic, phase-separated, membrane-less condensates in cells which often act as reaction centres in the cells. They can form in minutes and also dissolve as soon as the function is over. Importantly, these condensates form solid-like aggregates in neurodegeneration diseases. We try to understand the role of RNA in the formation, properties and function of the condensates in the cells.

Research Profile

Cellular microenvironment is compartmentalized into biomolecular condensates of RNA binding proteins (RBPs) and RNA, like nuclear-splicing speckles,  DNA repair sites and cytoplasmic stress granules. These condensates are dynamic which exchange components with the surrounding, behave like liquid droplets and are formed by a physicochemical process known as liquid-liquid phase separation. Changes in phase behaviour of condensates are associated with pathology in many neurodegenerative conditions. We focus on understanding the role of RNA interaction in the formation and function of biomolecular condensates.

The phase separation of the biomolecular condensates is known to be driven by low complexity domain containing RBPs and condensate-specific scaffold RNA. In cells the RBPs are always associated with RNAs the mammalian cells are filled with RNAs, around 20-30 picogram of RNA per cell. We found that the nucleus has a very high concentration of RNA which keeps many neurodegeneration-associated, prion-like RBPs in a soluble state. This also explains why these proteins often aggregate in the cytoplasm on mislocalization to the cytoplasm. Neurodegeneration is also associated with ageing and inflammation. We found that the condensates can also sequester endogenous immunogenic RNA and buffer inflammation. Taken together we want to understand the condensates from a molecular perspective as well as at the cellular and systems level. Specifically we are addressing the following questions in the coming years:

  1. How do condensates get specificity if they use very similar molecular grammar ?
  2. How does RNA metabolism change in ageing, cellular senescence and metabolic stress?
  3. Implication of large-scale RNA metabolic changes on condensate properties
  4. Map role of condensates in buffering mechanisms of immunogenic RNA

Seeing is believing and hence we develop in vitro and in cellular imaging modalities to map the dynamics of these condensates in regular fluorescence and super-resolution. We also explore these condensates in mammalin cell lines and in organismal tissue context.