NeuralCipher Research overview
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Transcription and mRNA processing are tightly coupled regulatory layers on gene expression, and their perturbations underly human disorders. X-linked Dystonia-Parkinsonism (XDP) is a unique example of a human disease connecting aberrant mRNA processing and the basal transcription machinery. XDP is a rare, monogenic fatal neurodegenerative disorder, and a limited understanding of the underlying molecular mechanisms hinders the development of effective therapies. In this study, we show that depletion of BRD4, a chromatin reader known for its role in transcriptional pausing, rescues the XDP molecular signature. Unexpectedly, this effect is independent of the canonical coactivator role of BRD4. We demonstrate that the XDP-SVA induces intronic premature cleavage and polyadenylation within the TAF1 locus, and that BRD4 depletion bypasses this premature termination checkpoint. These findings reveal new dimensions of BRD4 activity beyond transcription pause release and suggest modulation of mRNA processing as a therapeutic strategy for XDP.
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