TY - JOUR
T1 - Conserved and divergent gene regulatory programs of the mammalian neocortex
AU - Zemke, Nathan R.
AU - Armand, Ethan J.
AU - Wang, Wenliang
AU - Lee, Seoyeon
AU - Zhou, Jingtian
AU - Li, Yang Eric
AU - Liu, Hanqing
AU - Tian, Wei
AU - Nery, Joseph R.
AU - Castanon, Rosa G.
AU - Bartlett, Anna
AU - Osteen, Julia K.
AU - Li, Daofeng
AU - Zhuo, Xiaoyu
AU - Xu, Vincent
AU - Chang, Lei
AU - Dong, Keyi
AU - Indralingam, Hannah S.
AU - Rink, Jonathan A.
AU - Xie, Yang
AU - Miller, Michael
AU - Krienen, Fenna M.
AU - Zhang, Qiangge
AU - Taskin, Naz
AU - Ting, Jonathan
AU - Feng, Guoping
AU - McCarroll, Steven A.
AU - Callaway, Edward M.
AU - Wang, Ting
AU - Lein, Ed S.
AU - Behrens, M. Margarita
AU - Ecker, Joseph R.
AU - Ren, Bing
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12/14
Y1 - 2023/12/14
N2 - Divergence of cis-regulatory elements drives species-specific traits 1, but how this manifests in the evolution of the neocortex at the molecular and cellular level remains unclear. Here we investigated the gene regulatory programs in the primary motor cortex of human, macaque, marmoset and mouse using single-cell multiomics assays, generating gene expression, chromatin accessibility, DNA methylome and chromosomal conformation profiles from a total of over 200,000 cells. From these data, we show evidence that divergence of transcription factor expression corresponds to species-specific epigenome landscapes. We find that conserved and divergent gene regulatory features are reflected in the evolution of the three-dimensional genome. Transposable elements contribute to nearly 80% of the human-specific candidate cis-regulatory elements in cortical cells. Through machine learning, we develop sequence-based predictors of candidate cis-regulatory elements in different species and demonstrate that the genomic regulatory syntax is highly preserved from rodents to primates. Finally, we show that epigenetic conservation combined with sequence similarity helps to uncover functional cis-regulatory elements and enhances our ability to interpret genetic variants contributing to neurological disease and traits.
AB - Divergence of cis-regulatory elements drives species-specific traits 1, but how this manifests in the evolution of the neocortex at the molecular and cellular level remains unclear. Here we investigated the gene regulatory programs in the primary motor cortex of human, macaque, marmoset and mouse using single-cell multiomics assays, generating gene expression, chromatin accessibility, DNA methylome and chromosomal conformation profiles from a total of over 200,000 cells. From these data, we show evidence that divergence of transcription factor expression corresponds to species-specific epigenome landscapes. We find that conserved and divergent gene regulatory features are reflected in the evolution of the three-dimensional genome. Transposable elements contribute to nearly 80% of the human-specific candidate cis-regulatory elements in cortical cells. Through machine learning, we develop sequence-based predictors of candidate cis-regulatory elements in different species and demonstrate that the genomic regulatory syntax is highly preserved from rodents to primates. Finally, we show that epigenetic conservation combined with sequence similarity helps to uncover functional cis-regulatory elements and enhances our ability to interpret genetic variants contributing to neurological disease and traits.
UR - http://www.scopus.com/inward/record.url?scp=85179726588&partnerID=8YFLogxK
U2 - 10.1038/s41586-023-06819-6
DO - 10.1038/s41586-023-06819-6
M3 - Article
C2 - 38092918
AN - SCOPUS:85179726588
SN - 0028-0836
VL - 624
SP - 390
EP - 402
JO - Nature
JF - Nature
IS - 7991
ER -