Modeling gene expression trajectories in the developing brain: methods and applications

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Brain function and development depend on precise control of gene expression. Thousands of genes must be finely regulated both in spatial and temporal dimensions to achieve proper specialization and inter-connectivity of brain regions. Moreover, this regulation must be sustained throughout the long lifespan of neural cells, which in many cases is measured in years. Molecular processes related to transcription and RNA processing, thus, are particularly important for proper function of cells in the central nervous system. In recent years, the advances in genomic technologies have facilitated the generation of comprehensive transcriptomic and epigenomic developmental datasets from human tissues, which have been made publicly available. These international efforts provide a starting point for systematically assessing the complex molecular landscape throughout brain development and across brain regions and cell types. While some global analytical approaches have been developed, these large datasets remain largely unexplored. Fine grained dynamics of isoform expression and complex RNA processing mechanisms are still uncharacterized, and are the main focus of this proposal. Our overall goal is to study, at high temporal and spatial resolution, developmental regulation of transcriptional processes in the brain. We particularly focus on processes linking epigenetic (chromatin-related) and RNA processing mechanisms. For this, we propose to develop a model-based framework to describe expression trajectories of individual genes and exons across time and across brain regions. Within this framework, we aim to identify novel alternative exons, gene promoters, polyadenylation sites used exclusively in narrow developmental windows, and subsequently study the underlying chromatin-related determinants. Altogether, this program will have a direct impact on our understanding of fundamental mechanisms of transcription and epigenetic regulation of gene expression in the brain. Furthermore, the highly interdisciplinary approach we undertake will result in the development of expertise in integrated genomic analyses, open to the research community.