About the lab:

Developmental Chromatin Dynamics and Paralog Puzzle

A single-celled zygote gives rise to the entire human body, comprising several hundred specialized cell types with unique functions. Remarkably, despite their diversity, all these cells contain the same genetic material. What determines a cell’s identity is the specific set of genes it expresses, a process tightly regulated by cell type–specific enhancers. These enhancers are cis-regulatory elements located primarily within the non-coding regions that make up nearly 98% of our genome. Their activation is governed by a highly coordinated interplay of epigenetic factors, which includes transcription factors, chromatin remodelers, and co-activators, operating in a cell type–dependent manner. This dynamic regulation enables cells to respond precisely to developmental and environmental cues. However, the molecular mechanisms underlying this spatiotemporal regulation by chromatin remodelers is not fully understood.

At inStem, our lab focuses on the SWI/SNF (also known as BAF) chromatin remodeling complex, a multi-subunit, ATP-dependent enzyme that plays a critical role in gene regulation by modulating chromatin accessibility. While SWI/SNF is evolutionarily conserved from yeast to humans, vertebrate evolution has introduced substantial expansion in its subunit composition especially through the emergence of paralogous gene families. In mammals, many SWI/SNF subunits are encoded by such paralogs. The selective and mutually exclusive incorporation of these paralogous subunits results in the formation of hundreds of distinct SWI/SNF complex subtypes, the functions of which remain poorly understood in the context of embryonic stem cell pluripotency and early differentiation. Intriguingly, mutations in SWI/SNF subunits are frequently associated with developmental disorders, suggesting that proper regulation of lineage commitment is a critical safeguard during development. Our lab aims to uncover how specific combinations of SWI/SNF subunits contribute to enhancer activation and cell fate specification during early embryogenesis.

Key research questions:

1. How are SWI/SNF complex subtypes targeted to stage- and cell type–specific enhancers?
2. What roles do distinct SWI/SNF subtypes play in activating enhancers?
3. How do genetic perturbations in SWI/SNF paralogous subunits lead to developmental disorders?

We use a combination of CRISPR based genome engineering, targeted protein degradation, epi-genomics, proteomics and microscopy in stem cell differentiation models to uncover how these mechanisms regulate cell lineage specification/differentiation and contribute to developmental disorders.

Hiring:

If you’re excited about our research and looking for a project position or Master’s thesis project or internship, we’d love to hear from you! Just send your CV and a brief note about why you’re interested to animireddy@instem.res.in.

Interested in joining the lab as a Ph.D. student? Please apply through the inStem Graduate Program.