Cell Reports
Volume 17, Issue 12, 20 December 2016, Pages 3369-3384
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Cerebral Organoids Recapitulate Epigenomic Signatures of the Human Fetal Brain

https://doi.org/10.1016/j.celrep.2016.12.001Get rights and content
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Highlights

  • 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

Summary

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.

Keywords

DNA methylation
epigenome
organoid
brain development
3D culture

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Co-first author

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Present address: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK

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