Multi-omic profiling of the developing human cerebral cortex at the single cell level

INTRODUCTION: The functional complexity of the human brain depends on the interaction of heterogeneous populations of cell-types and sub-types. This cellular heterogeneity is established throughout development via dynamic changes in gene expression that are mediated, in part, by the spatiotemporal activity of cis-regulatory elements (CREs) found in cell-type specific patterns of accessible chromatin.

RATIONALE: To provide a better understanding of the molecular processes involved in human brain development, we simultaneously profiled gene expression and chromatin accessibility in individual nuclei isolated from frozen specimens of human cerebral cortex covering 6 broad developmental time-points (fetal (x2), newborn, childhood, adolescence and adulthood).

RESULTS: Joint analysis of transcriptomic and chromatin accessibility data from 45,549 individual nuclei led to the identification of genes and CREs with fundamental roles in lineage determination during cortical development. Our data suggests that dynamic changes in chromatin accessibility preceding transcript production is an important component of neuronal lineage commitment. We observed that lineage specific genes and chromatin accessible regions are enriched for neuropsychiatric disease associated risk loci, and, based on fine mapping analysis, implicate 152 putative risk genes in a range of disorders, including schizophrenia (SCZ), bipolar disorder (BD), attention deficit hyperactivity disorder (ADHD) and major depressive disorder (MDD).

CONCLUSION Multi-modal analysis of gene expression and chromatin accessibility in the developing human cortex facilitated improved taxonomy of major brain cell types across development, and led to the identification of novel disease associated regulatory domains and candidate genes. We present our data as an interactive web browser that can be utilized by the scientific community to explore spatiotemporal alterations in gene expression in brain development and neuropsychiatric disease.

Data access

Raw and processed data are available at GEO:GSE204684. You can view the open chromatin tracks in the UCSC genome browser and/or Single Cell Portal (SCP1859).