title: Cerebral Organoids Recapitulate Epigenomic Signatures of the Human Fetal Brain.
abstract: 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.
authors.affiliation: Genomic Analysis Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA; Howard Hughes Medical Institute, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Chongyuan
authors.initials: C
authors.lastname: Luo
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Vienna 1030, Austria.
authors.forename: Madeline A
authors.initials: MA
authors.lastname: Lancaster
authors.affiliation: Genomic Analysis Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Rosa
authors.initials: R
authors.lastname: Castanon
authors.affiliation: Genomic Analysis Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Nery
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Vienna 1030, Austria. Electronic address: juergen.knoblich@imba.oeaw.ac.at.
authors.forename: Juergen A
authors.initials: JA
authors.lastname: Knoblich
authors.affiliation: Genomic Analysis Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA; Howard Hughes Medical Institute, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: ecker@salk.edu.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Ecker
mesh_terms: D001921:Brain / Q000254:growth & development / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D057890:Epigenomics; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D009940:Organoids / Q000254:growth & development / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000378:metabolism*; D046509:Tissue Culture Techniques; D059467:Transcriptome / Q000235:genetics
keywords: 3D culture; DNA methylation; brain development; epigenome; organoid