Abstract
Human brain development is underpinned by cellular and molecular reconfigurations continuing into the third decade of life. To reveal cell dynamics orchestrating neural maturation, we profiled human prefrontal cortex gene expression and chromatin accessibility at single-cell resolution from gestation to adulthood. Integrative analyses define the dynamic trajectories of each cell type, revealing major gene expression reconfiguration at the prenatal-to-postnatal transition in all cell types followed by continuous reconfiguration into adulthood and identifying regulatory networks guiding cellular developmental programs, states, and functions. We uncover links between expression dynamics and developmental milestones, characterize the diverse timing of when cells acquire adult-like states, and identify molecular convergence from distinct developmental origins. We further reveal cellular dynamics and their regulators implicated in neurological disorders. Finally, using this reference, we benchmark cell identities and maturation states in organoid models. Together, this captures the dynamic regulatory landscape of human cortical development.
Original language | English |
---|---|
Pages (from-to) | 4428-4447.e28 |
Number of pages | 49 |
Journal | Cell |
Volume | 185 |
Issue number | 23 |
DOIs | |
Publication status | Published - 10 Nov 2022 |
Keywords
- brain disorders
- cerebral organoids
- development
- single-cell ATAC-seq
- single-cell RNA-seq
Cite this
- APA
- Author
- BIBTEX
- Harvard
- Standard
- RIS
- Vancouver
}
In: Cell, Vol. 185, No. 23, 10.11.2022, p. 4428-4447.e28.
Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Human prefrontal cortex gene regulatory dynamics from gestation to adulthood at single-cell resolution
AU - Herring, Charles A.
AU - Simmons, Rebecca K.
AU - Freytag, Saskia
AU - Poppe, Daniel
AU - Moffet, Joel J.D.
AU - Pflueger, Jahnvi
AU - Buckberry, Sam
AU - Vargas-Landin, Dulce B.
AU - Clément, Olivier
AU - Echeverría, Enrique Goñi
AU - Sutton, Gavin J.
AU - Alvarez-Franco, Alba
AU - Hou, Rui
AU - Pflueger, Christian
AU - McDonald, Kerrie
AU - Polo, Jose M.
AU - Forrest, Alistair R.R.
AU - Nowak, Anna K.
AU - Voineagu, Irina
AU - Martelotto, Luciano
AU - Lister, Ryan
N1 - Funding Information: This work was supported by the following grants: R.L.—National Health and Medical Research Council (NHMRC) Project Grant 1130168, NHMRC Investigator Grant 1178460 , Silvia and Charles Viertel Senior Medical Research Fellowship , Howard Hughes Medical Institute International Research Scholarship , and Australian Research Council (ARC) LE170100225 ; S.F.—NHMRC Ideas Grant 1184421; I.V.—ARC Future Fellowship FT170100359, UNSW Scientia Fellowship , and NHMRC Project Grant RG170137 ; S.B.—NHMRC-ARC Dementia Research Development Fellowship 1111206; C.P.—Raine Foundation Priming Grant RPG66-21; J.M.P.—Silvia and Charles Viertel Senior Medical Research Fellowship, ARC Future Fellowship FT180100674 . This work was supported by a Cancer Research Trust grant “Enabling advanced single cell cancer genomics in WA” and Cancer Council WA enabling grant . Genomic data were generated at the ACRF Centre for Advanced Cancer Genomics and Genomics WA. Human brain tissue was received from the UMB Brain and Tissue Bank at the University of Maryland, part of the NIH NeuroBioBank. The glioblastoma sample was procured and provided by the AGOG biobank, funded by CINSW grant SRP-08-10 . L.M. was a fellow of The Lorenzo and Pamela Galli Medical Research Trust. We thank Ankur Sharma and Greg Neely for valuable feedback. The graphical abstract and elements of Figure 1 A were created with BioRender. Funding Information: This work was supported by the following grants: R.L.—National Health and Medical Research Council (NHMRC) Project Grant 1130168, NHMRC Investigator Grant 1178460, Silvia and Charles Viertel Senior Medical Research Fellowship, Howard Hughes Medical Institute International Research Scholarship, and Australian Research Council (ARC) LE170100225; S.F.—NHMRC Ideas Grant 1184421; I.V.—ARC Future Fellowship FT170100359, UNSW Scientia Fellowship, and NHMRC Project Grant RG170137; S.B.—NHMRC-ARC Dementia Research Development Fellowship 1111206; C.P.—Raine Foundation Priming Grant RPG66-21; J.M.P.—Silvia and Charles Viertel Senior Medical Research Fellowship, ARC Future Fellowship FT180100674. This work was supported by a Cancer Research Trust grant “Enabling advanced single cell cancer genomics in WA” and Cancer Council WA enabling grant. Genomic data were generated at the ACRF Centre for Advanced Cancer Genomics and Genomics WA. Human brain tissue was received from the UMB Brain and Tissue Bank at the University of Maryland, part of the NIH NeuroBioBank. The glioblastoma sample was procured and provided by the AGOG biobank, funded by CINSW grant SRP-08-10. L.M. was a fellow of The Lorenzo and Pamela Galli Medical Research Trust. We thank Ankur Sharma and Greg Neely for valuable feedback. The graphical abstract and elements of Figure 1A were created with BioRender. R.L. conceived the study. R.L. S.F. C.A.H. R.K.S. and D.P. designed experiments and analyses. Sample preparation and data collection, R.K.S. D.P. D.B.V.-L. L.M. C.P. O.C. and J.M.P.; sequencing, D.P. and J.P.; data analysis and interpretation, C.A.H. S.F. R.K.S. D.P. S.B. O.C. C.P. A.A.-F. and R.L.; algorithm implementation, C.A.H. S.F. and J.M.P. Manuscript was written by R.K.S. S.F. C.A.H. D.P. S.B. and R.L. All authors approved of and contributed to the final manuscript. C.A.H. R.K.S. S.F. and D.P. contributed equally and have the right to list their name first in their CV. The authors declare no competing interests. Publisher Copyright: © 2022 The Authors
PY - 2022/11/10
Y1 - 2022/11/10
N2 - Human brain development is underpinned by cellular and molecular reconfigurations continuing into the third decade of life. To reveal cell dynamics orchestrating neural maturation, we profiled human prefrontal cortex gene expression and chromatin accessibility at single-cell resolution from gestation to adulthood. Integrative analyses define the dynamic trajectories of each cell type, revealing major gene expression reconfiguration at the prenatal-to-postnatal transition in all cell types followed by continuous reconfiguration into adulthood and identifying regulatory networks guiding cellular developmental programs, states, and functions. We uncover links between expression dynamics and developmental milestones, characterize the diverse timing of when cells acquire adult-like states, and identify molecular convergence from distinct developmental origins. We further reveal cellular dynamics and their regulators implicated in neurological disorders. Finally, using this reference, we benchmark cell identities and maturation states in organoid models. Together, this captures the dynamic regulatory landscape of human cortical development.
AB - Human brain development is underpinned by cellular and molecular reconfigurations continuing into the third decade of life. To reveal cell dynamics orchestrating neural maturation, we profiled human prefrontal cortex gene expression and chromatin accessibility at single-cell resolution from gestation to adulthood. Integrative analyses define the dynamic trajectories of each cell type, revealing major gene expression reconfiguration at the prenatal-to-postnatal transition in all cell types followed by continuous reconfiguration into adulthood and identifying regulatory networks guiding cellular developmental programs, states, and functions. We uncover links between expression dynamics and developmental milestones, characterize the diverse timing of when cells acquire adult-like states, and identify molecular convergence from distinct developmental origins. We further reveal cellular dynamics and their regulators implicated in neurological disorders. Finally, using this reference, we benchmark cell identities and maturation states in organoid models. Together, this captures the dynamic regulatory landscape of human cortical development.
KW - brain disorders
KW - cerebral organoids
KW - development
KW - single-cell ATAC-seq
KW - single-cell RNA-seq
UR - http://www.scopus.com/inward/record.url?scp=85141493588&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2022.09.039
DO - 10.1016/j.cell.2022.09.039
M3 - Article
C2 - 36318921
AN - SCOPUS:85141493588
SN - 0092-8674
VL - 185
SP - 4428-4447.e28
JO - Cell
JF - Cell
IS - 23
ER -