National Institute on Deafness and Other Communication Disorders PA-23-272

How genome architecture controls Protocadherin gene choice at single-allele resolution

The award funds research to understand how genome architecture regulates Protocadherin gene expression in neurons, using advanced imaging and genetic models, with implications for brain development and neuropsychiatric disorder therapies.

Description

This project aims to generate a molecular understanding of how Protocadherin (Pcdh) genes are regulated across neurodevelopment, which could enable the development of therapeutics to address neural wiring defects. The study will use optical reconstruction of chromatin architecture (ORCA) to image single-allele genome structure in neurons of the olfactory epithelium and their precursors, establish a developmental clock of Pcdh gene choice linking 3D genome folding to Pcdh expression onset, study cohesin's role in controlling Pcdh choice using genetic mouse models, and investigate how heterochromatin stabilizes Pcdh gene expression across the neuron’s lifespan. Implications include insights into brain wiring, gene regulation, and potential therapeutic avenues for neuropsychiatric and neurodegenerative disorders such as schizophrenia and autism.

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