Investigating the regulation of chromatin associated proteins by intrinsically disordered regions

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Each cell in a multi-cell organism originally contains a full copy of the genome in its nucleus, but only a subset of these genes is active and in use. Proper regulation of which genes are on, and which are off, in each cell is critical to steer development and all basic body functions. The genome does not exist as naked DNA but is wrapped around complexes of proteins called histones, which together with the DNA form so-called chromatin. Gene regulation is in large part dictated by how this chromatin is packaged around individual genes, which is in turn controlled by various large protein complexes in the nucleus. A critical aspect of these protein complexes’ function is the ability to read post-translational modifications (PTMs) on the histones, which act as labels to guide them to the correct place. However, how these PTMs contribute to this process is still poorly understood within the overall complexity of chromatin. This project addresses fundamental questions of how histone PTM readout in a chromatin context is regulated by highly conserved elements within these chromatin-binding proteins to control proper gene transcription during development. In addition to the scientific goals, the PIs will work closely with a local commuter college to recruit and retain young students from underrepresented groups into the sciences. They will also work to enhance communication between the scientific and lay communities by encouraging the use of art in this conversation, through participation in the Art of Science Fellowship. The questions addressed in this project are fundamentally important for understanding how histone PTM readout is regulated in the chromatin context. Specifically, this project will investigate how evolutionarily conserved, intrinsically disordered regions (IDRs) found adjacent to histone reader domains regulate nucleosome dynamics, histone PTM readout, transcription, and development. The mechanistic basis of this regulation will be uncovered using a series of NMR spectroscopy experiments on conserved IDRs-reader pairs. This project will test the functional importance of these IDRs in vivo using an allelic series of zebrafish mutants. Selective removal and substitution of these deeply conserved amino acid residues and comparison to loss-of-function alleles will allow, for the first time, testing of the developmental and physiological contribution of these IDRs. This project was supported jointly by Molecular Biophysics and Genetic Mechanism Clusters of the Division of Molecular and Cellular Biosciences.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.