TY - JOUR
T1 - Single-cell epigenomics reveals mechanisms of human cortical development
AU - Ziffra, Ryan S.
AU - Kim, Chang N.
AU - Ross, Jayden M.
AU - Wilfert, Amy
AU - Turner, Tychele N.
AU - Haeussler, Maximilian
AU - Casella, Alex M.
AU - Przytycki, Pawel F.
AU - Keough, Kathleen C.
AU - Shin, David
AU - Bogdanoff, Derek
AU - Kreimer, Anat
AU - Pollard, Katherine S.
AU - Ament, Seth A.
AU - Eichler, Evan E.
AU - Ahituv, Nadav
AU - Nowakowski, Tomasz J.
N1 - Funding Information:
Acknowledgements We thank A. Bhaduri for help with generation of scRNA-seq data and its analysis, and discussions throughout the project; M. Andrews for sharing organoid cultures; M. Song and Y. Shen for sharing PLAC–seq promoter-interacting regions for intersection with our data; and J. Rubenstein for reading of the manuscript. This study was supported by NIH awards: psychENCODE award U01MH116438, Brain Initiative award U01MH114825, and the Psychiatric Cell Map Initiative Convergence Neuroscience award U01MH115747, NIMH award R01MH109907 (N.A. and K.S.P.), an Autism Speaks Predoctoral Fellowship (11874 to R.S.Z.), a Simons Foundation grant (SFARI 491371 to T.J.N.), an NARSAD Young Investigator Grant (to T.J.N.), gifts from Schmidt Futures and the William K. Bowes Jr Foundation, the Gladstone Institutes, the National Institute of Mental Health (1K99MH117165 to T.N.T.), the US NIH (R01 MH101221 to E.E.E.) and 5U41HG002371-19 to M.H.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/10/7
Y1 - 2021/10/7
N2 - During mammalian development, differences in chromatin state coincide with cellular differentiation and reflect changes in the gene regulatory landscape1. In the developing brain, cell fate specification and topographic identity are important for defining cell identity2 and confer selective vulnerabilities to neurodevelopmental disorders3. Here, to identify cell-type-specific chromatin accessibility patterns in the developing human brain, we used a single-cell assay for transposase accessibility by sequencing (scATAC-seq) in primary tissue samples from the human forebrain. We applied unbiased analyses to identify genomic loci that undergo extensive cell-type- and brain-region-specific changes in accessibility during neurogenesis, and an integrative analysis to predict cell-type-specific candidate regulatory elements. We found that cerebral organoids recapitulate most putative cell-type-specific enhancer accessibility patterns but lack many cell-type-specific open chromatin regions that are found in vivo. Systematic comparison of chromatin accessibility across brain regions revealed unexpected diversity among neural progenitor cells in the cerebral cortex and implicated retinoic acid signalling in the specification of neuronal lineage identity in the prefrontal cortex. Together, our results reveal the important contribution of chromatin state to the emerging patterns of cell type diversity and cell fate specification and provide a blueprint for evaluating the fidelity and robustness of cerebral organoids as a model for cortical development.
AB - During mammalian development, differences in chromatin state coincide with cellular differentiation and reflect changes in the gene regulatory landscape1. In the developing brain, cell fate specification and topographic identity are important for defining cell identity2 and confer selective vulnerabilities to neurodevelopmental disorders3. Here, to identify cell-type-specific chromatin accessibility patterns in the developing human brain, we used a single-cell assay for transposase accessibility by sequencing (scATAC-seq) in primary tissue samples from the human forebrain. We applied unbiased analyses to identify genomic loci that undergo extensive cell-type- and brain-region-specific changes in accessibility during neurogenesis, and an integrative analysis to predict cell-type-specific candidate regulatory elements. We found that cerebral organoids recapitulate most putative cell-type-specific enhancer accessibility patterns but lack many cell-type-specific open chromatin regions that are found in vivo. Systematic comparison of chromatin accessibility across brain regions revealed unexpected diversity among neural progenitor cells in the cerebral cortex and implicated retinoic acid signalling in the specification of neuronal lineage identity in the prefrontal cortex. Together, our results reveal the important contribution of chromatin state to the emerging patterns of cell type diversity and cell fate specification and provide a blueprint for evaluating the fidelity and robustness of cerebral organoids as a model for cortical development.
UR - http://www.scopus.com/inward/record.url?scp=85116401453&partnerID=8YFLogxK
U2 - 10.1038/s41586-021-03209-8
DO - 10.1038/s41586-021-03209-8
M3 - Article
C2 - 34616060
AN - SCOPUS:85116401453
SN - 0028-0836
VL - 598
SP - 205
EP - 213
JO - Nature
JF - Nature
IS - 7879
ER -