Multi-omic profiling of the developing human cerebral cortex at the single cell level [snATAC-seq]

Human brain development starts during embryogenesis and extends postnatally to adulthood. During this time, the cellular complexity of the brain is established via dynamic changes in gene expression, mediated, in part, by the spatiotemporal activity of cis-regulatory elements. To better understand these processes, we performed simultaneous profiling of gene expression and chromatin accessibility in 45,549 individual nuclei, isolated from the human cortex across 6 broad developmental time-points from fetus to adult. We identified cell-type specific domains in which chromatin accessibility is highly correlated with gene expression. Differentiation pseudotime trajectories of gene expression in neuronal subpopulations indicate that chromatin accessibility at cis-regulatory elements precedes transcription and that dynamic changes in chromatin structure play a critical role in neuronal lineage commitment. In addition, using lineage-specific genes and peaks, we mapped cell-type specific genetic loci implicated in neuropsychiatric traits, including schizophrenia, major depressive disorder and bipolar disorder. Together, our results describe the complex regulation of cell composition at critical stages in lineage determination, serve as a developmental blueprint of the human brain and shed light on the impact of spatiotemporal alterations in gene expression on neuropsychiatric disease. snATAC-seq