Sunday, April 28, 2024
4/28/2024
PROJECT SUMMARY/ABSTRACT Biological processes on nuclear DNA occur in the context of chromatin. The precise regulation of transcription, DNA replication, and DNA damage repair requires dynamic control of histone mobility orchestrated by chromatin regulation. The multiple roles of chromatin regulation in neurodevelopment are being unraveled. Recent studies have revealed that cell fate specification, neural plasticity, and circuit formation are mediated, in part, by chromatin. Mechanistically, chromatin modulates these developmental processes via transcriptomic regulation. Chromatin, however, also plays an essential role in genome maintenance. Genome integrity is particularly important in rapidly dividing stem cells, including neural progenitor cells (NPCs). DNA replication and DSB repair each occur in the context of chromatin, which must be reorganized for all transactions on DNA, including replication fork progression, DSB detection, and recruitment of DNA repair factors. These processes are mediated by chromatin remodelers – ATP-dependent protein complexes that can reposition nucleosomes on DNA, evict nucleosomes from DNA, or exchange histone subunits, thus controlling the accessibility, flexibility, and mobility of chromatin. In striking contrast to the well-known transcriptional roles of chromatin, the equally important functions of chromatin regulation in genome maintenance are virtually unexplored in neural development. Here, the proposed work builds on our recent paper on the chromatin remodeler Ino80 (Keil et al., 2020), in which we find dissociable roles for Ino80 in YY1-associated transcriptional regulation and homologous recombination (HR) DNA repair in cortical NPCs. Notably, impaired DNA repair is the driver of neuroanatomical phenotypes following Ino80 deletion, thus demonstrating that this underexplored role of chromatin can effect neurodevelopmental consequences. Importantly, Ino80’s DNA repair function is not unique among chromatin remodelers. In this application, we seek to investigate a potentially wider role of chromatin remodeling in DNA damage and repair in NPCs. We will apply our expertise in chromatin biology, DNA damage repair, functional genomics, and genetics to: 1) dissect distinct chromatin remodeling functions in transcriptional regulation versus genome maintenance; 2) determine the mechanisms of chromatin remodeling functions in DNA replication and damage repair; and 3) assess the brain somatic genome consequences of chromatin remodeling dysfunction. Recent human genetic findings have convergently implicated chromatin dysregulation in neurodevelopmental disorders. Here, we propose that, in addition to transcriptional regulation, chromatin remodeling plays an equally important role in genome stability across NPC divisions. This aspect of chromatin function is largely unexplored in brain development. Our study will address this important gap in the field and mechanistically dissect the distinct roles of chromatin remodeling in transcriptional regulation versus genome maintenance in neurodevelopment.
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