A ring-shaped protein complex called cohesin normally holds DNA in tightly folded loops, but when the complex breaks, it triggers a rare developmental disorder called Cornelia de Lange Syndrome (CdLS). The problem is that cohesin is active in every cell, yet CdLS only damages specific tissues—heart, limbs, and brain—and no one understands why. This project will map which genes are most sensitive to cohesin disruption by analysing individual cells from CdLS mouse models, then check whether the same genes are misfolded in patient tissue samples. If the researcher can identify the common chromatin folding features that make certain genes vulnerable, it would explain why a single broken protein causes such precise damage. This is fundamental science: it will not produce a treatment tomorrow. But understanding how chromatin disruption targets specific tissues could eventually guide drug development for CdLS and for dozens of other developmental diseases caused by similar chromatin protein mutations.
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More than 100 chromatin proteins have been identified as causative genes in human genetic disease. Most of these genes are broadly expressed and have fundamental roles in transcriptional regulation, yet their disruption causes tissue-specific effects. We do not understand the molecular basis of this tissue-specificity, as it has been challenging to identify the specific cell types affected and to study the consequences of these mutations in the proper tissue context. I will focus on Cornelia de Lange Syndrome (CdLS), a genetic disorder of cohesin function. Cohesin is a ring-shaped protein complex that encircles DNA and stabilises the 3D folding of chromatin. Mutations in cohesin complex members are thought to disrupt chromatin folding and impair cells’ ability to properly regulate gene expression. This project will determine which genes are particularly cohesin-sensitive and lead to the tissue-specific pathologies of CdLS. I will identify dysregulated genes by applying single-cell and spatial transcriptomics to CdLS mouse models. I will find common chromatin folding features of these genes using genome architecture mapping and look for similar patterns of disruption in banked CdLS patient samples. This project will lay the foundations for a broad research programme exploring chromatin disruption in other developmental diseases.
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