Chromatin Mechanisms of Corticogenesis

The remarkable complexity of the mammalian brain arises from precisely regulated genetic programs that control neural cell number and diversity during embryonic development. Epigenetic mechanisms—heritable modifications that influence gene expression without changing the DNA sequence—are central to orchestrating these programs. However, how epigenetic regulation in neural stem cells determines neuronal number and diversity in the developing brain remains poorly understood. This proposal addresses this critical gap by leveraging sophisticated mouse genetic models and cutting-edge DNA sequencing technologies to investigate the role of epigenetic modifications in cerebral cortex development. The resulting insights will deepen our fundamental understanding of mammalian, including human, cortical development. Furthermore, this work will illuminate how disruptions in epigenetic regulation contribute to the cellular and molecular defects underlying some neurodevelopmental disorders, such as autism. Complementing the research, the proposal includes a comprehensive educational initiative to engage and train high school students, teachers, and both undergraduate and graduate students in the fields of genomics, epigenetics, and neurodevelopment. Central to understanding developmental cell commitment is elucidating how epigenetic mechanisms silence alternative cell fates. These mechanisms, mediated by chemical modifications in chromatin, play a crucial role in regulating gene expression programs. A defining feature of transcriptionally silent chromatin (heterochromatin) is the di- and tri-methylation of histone H3 at lysine 9 (H3K9me2 and H3K9me3). Previous studies indicate that H3K9-methylated heterochromatin acts as a barrier to cell fate conversions, underscoring its critical role in promoting cell commitment and preserving cell identity. However, how distinct H3K9 methylation states regulate neurogenesis and cell fate specification in the developing mammalian brain remains unknown. Here, we generated mouse genetic models to deplete H3K9me2 or H3K9me3 in the embryonic cerebral cortex. Our preliminary data show that H3K9me2 and H3K9me3 occupy distinct chromatin regions and control different aspects of cortical neurogenesis. In this proposal, we will dissect the molecular mechanisms of gene silencing by H3K9me2/3 in the cortical lineage. These insights will advance our understanding of neurodevelopmental disorders in which H3K9-methylated heterochromatin may play a central role. This project is jointly funded by the Genetic Mechanisms Program of the Division of Molecular and Cellular Biosciences (MCB) and by the Neural Systems Program of the Division of Integrative Organismal Systems (IOS) in the Directorate for Biological Sciences (BIO). 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.