Deciphering the mechanism through which BRD4 mutations contribute to the neurodevelopmental disorder

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Epigenetic proteins, including writers and readers of histone posttranslational modifications and chromatin remodelling proteins, play an essential role in the controlled tissue-specific regulation of gene expression. Acetylation of histone lysines is one of the most abundant modifications which alters chromatin structure and function. A delicate balance between lysine acetylation and deacetylation is essential for the normal functioning of the central nervous system. Gene mutations that perturb the histone acetylation pathway cause many neurodevelopmental disorders, warranting detailed investigation into the specific role of the acetylation pathway in the central nervous system. Recently we have discovered that mutations in gene encoding histone acetylation reader protein BRD4 lead to a neurodevelopmental disorder. However, it is not clear how mutations in this gene encoding epigenetic factor lead to specific neurodevelopmental disorders. We aim to investigate how mutations in BRD4 cause altered development and functioning of the central nervous system. We will first identify genes regulated by BRD4 in human neuronal cell types. We will then identify neuronal-specific enhancers regulated by BRD4 and link these enhancers to target genes that are dysregulated upon depletion or mutation in BRD4. Next, we will investigate how patient-specific mutations in BRD4 cause an altered transcriptional programme by performing single-cell transcriptomics and epigenetic alterations in the mini-brain organoid model. Furthermore, we will test the efficacy of epigenetic drugs in rescuing the altered brain development phenotype and functioning due to BRD4 mutations. Overall, this proposal aims to uncover the role of BRD4 in human brain development and function and how BRD4 mutations lead to specific neurodevelopmental disorders.