Cerebral Organoids Recapitulate Epigenomic Signatures of the Human Fetal Brain

• Published in: Cell reports (Cambridge) Vol. 17; no. 12; pp. 3369 - 3384
• Main Authors: Luo, Chongyuan, Lancaster, Madeline A., Castanon, Rosa, Nery, Joseph R., Knoblich, Juergen A., Ecker, Joseph R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.12.2016; Elsevier
• Subjects: 3D culture; Brain - growth & development; Brain - metabolism; brain development; Cell Differentiation - genetics; DNA methylation; DNA Methylation - genetics; epigenome; Epigenomics; Gene Expression Regulation, Developmental; Humans; organoid; Organoids - growth & development; Organoids - metabolism; Pluripotent Stem Cells - metabolism; Tissue Culture Techniques; Transcriptome - genetics; brain development; DNA methylation; epigenome; 3D culture; organoid
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.12.001

Organoids derived from human pluripotent stem cells recapitulate the early three-dimensional organization of the human brain, but whether they establish the epigenomic and transcriptional programs essential for brain development is unknown. We compared epigenomic and regulatory features in cerebral organoids and human fetal brain, using genome-wide, base resolution DNA methylome and transcriptome sequencing. Transcriptomic dynamics in organoids faithfully modeled gene expression trajectories in early-to-mid human fetal brains. We found that early non-CG methylation accumulation at super-enhancers in both fetal brain and organoids marks forthcoming transcriptional repression in the fully developed brain. Demethylated regions (74% of 35,627) identified during organoid differentiation overlapped with fetal brain regulatory elements. Interestingly, pericentromeric repeats showed widespread demethylation in multiple types of in vitro human neural differentiation models but not in fetal brain. Our study reveals that organoids recapitulate many epigenomic features of mid-fetal human brain and also identified novel non-CG methylation signatures of brain development. [Display omitted] •In vitro and in vivo brain development share epigenomic signatures•Extracellular matrix gene expression distinguishes 2D versus 3D differentiation methods•Non-CG methylation marks the forthcoming repression of super-enhancers•Pervasive demethylation of peri-centromeric regions occurs in human neural cultures Luo et al. find extensive shared epigenomic patterns during in vitro and in vivo brain development. The analysis of cerebral organoids identifies non-CG DNA methylation signatures of brain development, demonstrating its utility as a model for brain epigenomics.