The RNA Biology Lab cultures pluripotent stem cells to develop cerebral organoids (or ‘mini brains’). These 'organs on a dish' recapitulate the developmental plasticity of an actual mammalian brain and can be used as a great model for studying development, modeling disease pathophysiology, and discovering novel drug molecules. Cerebral organoids have a lot of potential in personalized medicine and therapy when developed from patient-specific induced pluripotent stem cells (iPSCs). Along with the labs of Souvik Maiti and Beena Pillai, we are testing small molecules involved in the growth and proliferation of mouse organoids.

 

The developed models are currently being used to understand the disease pathogenesis of Megalencephalic Leukoencephalopathy (MLC) and Spinocerebellar Ataxia (SCA) Type 17 to create disease models. These models would better simulate the disease characteristics in patients and thereafter be applied for CRISPR-Cas-based gene editing for the potential treatment of these diseases. We are currently focusing on neuronal migration inside the brain that occurs at the time of development. through assembloids (fused ventral and dorsal forebrain organoids). After attaining their position, neurons form circuits by interconnecting with each other and start acting as the basic building blocks of any brain activity that executes behavior. Any issues in circuitry could result in malformed behaviors as seen in diseases like Autism, Schizophrenia, and Epilepsy.  Another exciting area of research in the lab is to study the role of lncRNAs and their regulation during early neuronal development using cortical spheroids. 

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RNA Signatures in Cell-Fate Decisions

Embryonic Stem Cells (ESCs) exhibit the nature of pluripotency and developmental plasticity. Originally, from the inner cell mass of a human blastocyst, they have the potential to differentiate into every other cell or tissue type be it a neuron or a hepatocyte. By providing appropriate conditions in vitro, they can be made to proliferate indefinitely. This property can be manipulated for various therapeutic applications such as disease modeling and personalized medicine via lineage commitment. An embryonic stem cell can be subjected to a specific lineage by tweaking associated controlling factors.

 

In our lab, we have extensively studied such environmental cues and pluripotency regulators, particularly the splicing factor TOBF1. The overexpression or downregulation of this RNA-binding protein has been shown to interfere with the maintenance of embryonic stem cell identity. Our recent studies on TOBF1 chromatin occupancy, associated OCT-SOX binding motifs, and transcripts that undergo alternative splicing upon its disruption have helped unmask their local nuclear territories. In recent years, owing to the development of better strategies to identify and study them, lncRNAs have been implicated in a variety of different cellular pathways including disease progression. We are interested in studying functional lncRNAs that are implicated in certain types of cancer in the Indian population and developing strategies to utilize them as molecular biomarkers for early diagnosis and better prognostics. The long-non-coding RNA Panct1 interacts with TOBF1 and localizes to OCT-SOX motifs in a specific cell-cycle regulated manner and helps maintain the identity of embryonic stem cells in mice. The associated mechanistic pathways are also being explored with regard to various genetic diseases.