PsychENCODE and beyond: transcriptomics and epigenomics of brain development and organoids

Crucial decisions involving cell fate and connectivity that shape the distinctive development of the human brain occur in the embryonic and fetal stages—stages that are difficult to access and investigate in humans. The last decade has seen an impressive increase in resources—from atlases and databases to biological models—that is progressively lifting the curtain on this critical period. In this review, we describe the current state of genomic, transcriptomic, and epigenomic datasets charting the development of normal human brain with a particular focus on recent single-cell technologies. We discuss the emergence of brain organoids generated from pluripotent stem cells as a model to compensate for the limited availability of fetal tissue. Indeed, comparisons of neural lineages, transcriptional dynamics, and noncoding element activity between fetal brain and organoids have helped identify gene regulatory networks functioning at early stages of brain development. Altogether, we argue that large multi-omics investigations have pushed brain development into the “big data” era, and that current and future transversal approaches needed to leverage both fetal brain and organoid resources promise to answer major questions of brain biology and psychiatry.