Transcriptome and epigenome landscape of human cortical development modeled in organoids

TLDR

Genes linked to neuropsychiatric disorders are active in the human fetal brain but are difficult to study longitudinally. The study uses organoids to identify functional elements that may drive disease onset. Organoid‑derived multiomics data show that cerebral cortical development before 16 weeks is recapitulated, with major gene and enhancer changes at the stem‑to‑progenitor transition, distinct expression/activity patterns, and modules enriched for human‑gained enhancers and autism‑associated genes.

Abstract

Genes implicated in neuropsychiatric disorders are active in human fetal brain, yet difficult to study in a longitudinal fashion. We demonstrate that organoids from human pluripotent cells model cerebral cortical development on the molecular level before 16 weeks postconception. A multiomics analysis revealed differentially active genes and enhancers, with the greatest changes occurring at the transition from stem cells to progenitors. Networks of converging gene and enhancer modules were assembled into six and four global patterns of expression and activity across time. A pattern with progressive down-regulation was enriched with human-gained enhancers, suggesting their importance in early human brain development. A few convergent gene and enhancer modules were enriched in autism-associated genes and genomic variants in autistic children. The organoid model helps identify functional elements that may drive disease onset.