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Dan Weinberg F30 Application Awarded January 15th, 2018



"Perturbation of Polycomb-mediated gene repression by histone H3 mutations"

Recurrent missense mutations in genes encoding histone H3 that substitute lysine to methionine (H3 "K-to-M" mutations) were recently identified in multiple types of human cancer including diffuse intrinsic pontine glioma (H3K27M) and a subset of head and neck squamous cell carcinomas and undifferentiated pediatric sarcomas (H3K36M) that together are characterized by poor prognosis and have few effective treatment options. Biochemical and structural data indicate that H3K27M and H3K36M dominantly inhibit the specific histone methyltransferases for each lysine in trans. However, how these histone mutants promote malignant transformation is largely unknown, with initial work implicating aberrant gene regulation by Polycomb repressive complexes in cells expressing either mutation. The proposed study aims to gain mechanistic insight into the chromatin landscape changes induced by H3 "K-to-M" mutations that perturb Polycomb-mediated gene repression to drive oncogenesis, which will provide a basis for developing new therapeutic strategies.





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