Deciphering the Regulatory Logic of Cortical Development

The mammalian cortex is the most complex region of the brain responsible for higher cognitive functions. Abnormal cortical development often translates into prominent neuropsychiatric diseases, which affect different neuronal subtypes with unique molecular and morphological features. Increasing evidence suggests that epigenetic regulation is essential for cortical development but how multiple regulatory layers are coordinated to specify distinct neuronal lineages in vivo remains unclear.My team and I recently applied single-cell RNA-seq, single-cell ATAC-seq together with cell-type-specific DNA methylation and 3D genome measurements to map the regulatory landscape of neural differentiation at a single embryonic stage in vivo. However, the process of neuronal subtype specification involves multiple distinct waves of differentiation over several consecutive days. Therefore, to decode the molecular logic of temporal cellular identity in the cortex, I will comprehensively dissect the interplay between gene expression, chromatin topology and epigenetics in specifying cell fate. In order to accomplish this, I will build upon my extensive experimental and computational expertise to (1) map the regulatory landscape of the developing mouse cortex across multiple regulatory layers and timepoints in single cells; (2) identify and validate cis-regulatory elements via a novel massive parallel cell-type specific reporter assay in vivo and (3) determine the functional consequences of perturbing enhancers and silencers using a highly multiplexed single-cell approach. Collectively, EpiCortex will provide unprecedented insights and establish new paradigms into the interplay between transcription factors, epigenome dynamics and gene expression in development. It will allow us to better understand the molecular logic of lineage specification in the mammalian cortex and more precisely define, compare and ultimately engineer cellular identities for therapeutic and regenerative purposes