Our Research Goals and Pipelines

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Chromatin regulation of nervous system development in health and disease

A molecular view into cellular neurodevelopmental outcomes

The cerebral cortex is the seat of sensory perception, decision-making, language, learning and memory. How this complex structure is brought about during development is a fascinating question in neurobiology. Chromatin and epigenetic regulations play a fundamental and critical role in cortical development. Studying the chromatin regulatory mechanisms is important to our understanding of the fundamental process of building the brain and it is mutations in the very same networks, which lead to a range of neurodevelopmental disorders.

Our lab’s broad research aim is to understand chromatin-level control of brain development in health and in disease. With our study, we would like to create a molecular and cellular understanding of neurobiological pathways underlying neurodevelopmental and neuropsychiatric disorders to enable future data-driven precision diagnostics and therapies for patients (see image above).

 

A few research questions we ask spanning the fields of fundamental developmental neuroscience, neurodevelopmental and neuropsychiatric syndromes, are as below.

 

Basic Research in Cortical Stem cell biology

 

  1. Dynamic interaction of Chromatin Remodellers and Transcription factors to build the Cerebral Cortex

The various neurons and glia in the cerebral cortex are all derived from divisions of the diverse cortical progenitors or cortical stem cells.

Sequential molecular transcriptional programs generate the neurons and glia which then make very specific local and long-range circuit connections leading to behaviour in the adult. Thus the emergent function in the brain starts from molecules and cells ultimately leading to behaviour.

Current hypothesis in the field of genomic regulation is that gene expression is modulatory and is thus a dynamic and multistep process (concept of the Probabilistic genome reviewed by Tom Misteli, 2020, Cell)

We would like to understand the dynamic nature of the molecular interactions of chromatin modifiers and transcription factors that leads to modulatory gene expression of downstream targets and thereby produce the diverse neuronal and glial subtypes in the cerebral cortex.

 

Clinical Research in Neurodevelopmental (NDD) and Neuropsychiatric disorders

 

  2. Mechanisms of Dysregulation underlying Chromatinopathy leading to Intellectual Disability

 

Chromatin modifiers are frequently mutated in NDDs. Such disorders are known as Chromatinopathies. Our molecular and cellular understanding of such disorders is poor primarily because the causative role of these mutations and the mechanistic details of the deregulation caused by these pathogenic mutations have not been characterized yet. We would like to delineate how putative risk variants in a chromatin remodeler, as found in a rare form of intellectual disability, could impair cerebral cortical development and be causative of the illness. 

 

  3. Mechanisms of Neuropathology in Neuropsychiatric patients from Clinically Dense Indian Families

 

Mental illnesses like schizophrenia and bipolar disorder pose a huge socio-economic burden on patients. Yet, neuropsychiatric illnesses lack targeted medical therapies. We utilize the resources created by an interdisciplinary program of work, the Accelerator program for Discovery in Brain disorders using Stem cells (ADBS) to obtain mechanistic insights into the cellular basis of neuropsychiatric illness. This unique study has assembled a cohort of 300 families that are clinically dense for mental illness. Such families enable the discovery of rare penetrative variants and their role in neuropathology. We would like to identify disruptive gene variants and decipher the impaired molecular neurobiological pathways in neuropsychiatric illness to facilitate the development of effective therapeutics and clinical management of these disorders.

 

Technologies and model systems

 

We use mouse to study conserved cellular and molecular mechanisms of cerebral cortical development and use human induced pluripotent stem cells (iPSCs) derived neurons and cerebral organoids to study human specific, and patient genetic background-specific, neuropathological mechanisms of neurodevelopmental disorders.

Our work takes us from understanding at the molecular level to neurons and glia to neurocircuits underlying behaviour.

We use an exhaustive range of technologies and methods to achieve the granularity at each level of our understanding of the emergent function of the nervous system.

 

We combine mouse genetics with functional genomics (Transcription factor ChIP-seq, ATAC-seq, RNA-seq and Histone ChIP-seq) and protein biochemistry to identify downstream target genes and their interacting partners. For functional and cellular analysis of the identified target genes we perform, in utero electroporation, organotypic slice cultures, dissociated neuron/glia culture and retrograde and anterograde labelling of axon tracts to examine connectivity in mice brain.

For studying human specific mechanisms we generate 2D neuron/glia cultures and 3D cerebral organoids and combine CRISPR-Cas gene editing to model neuropsychiatric disorders in a dish. We perform single cell-RNA-seq from organoids at critical stages of neural development to identify neural cell type specific transcriptomic changes.

Overarching objective

Funding

Our research is supported by core funds from inStem, Har Gobind Khorana IYBA grant from Dept. of Biotechnology (GoI), Start-up Research Grant from SERB- Dept. of Science and Technology (GoI), and Intermediate Career fellowship from the DBT/Wellcome Trust India Alliance.