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

Abstract

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.

Fig. 1. Integrative approaches to study human brain development.

a Illustration of two complementary models, postmortem human brain tissue and iPSC-derived brain organoids. b Potential of multi-omics approaches to connect/integrate genomic, transcriptomic, and epigenomic information generated or available through datasets of in vivo/in vitro studies. Enhancer activity (identified from ATAC-seq, ChIP-seq) influences transcription (RNA-seq) of gene/s through DNA looping (identified through Hi-C). Similarly, eQTL connects risk variants (discovered via DNA-seq, SNPs, GWAS) to gene expression. These variants may disrupt transcription factor binding sites (TFBS) within enhancers. Human-specific gene regulatory mechanisms can be validated in live cell systems, i.e., iPSC-derived organoids, or human progenitor cell lines, by high throughput methods (e.g., MPRA, STARR-seq). c Studying gene-enhancer dynamics over time both in vivo and in organoids (ORG) can reveal biological insight into the formation and evolution of the human brain (e.g., the hourglass shape of interregional diversity over time between cortex (CTX), striatum (STR), cerebellum (CRB)). d Single-cell omics can define those dynamics at the cellular levels, for instance revealing how gene regulation evolves between radial glia (RG) and neuronal derivatives (N1, N2).