Conserved and divergent gene regulatory programs of the mammalian neocortex

Nathan R. Zemke, Ethan J. Armand, Wenliang Wang, Seoyeon Lee, Jingtian Zhou, Yang Eric Li, Hanqing Liu, Wei Tian, Joseph R. Nery, Rosa G. Castanon, Anna Bartlett, Julia K. Osteen, Daofeng Li, Xiaoyu Zhuo, Vincent Xu, Lei Chang, Keyi Dong, Hannah S. Indralingam, Jonathan A. Rink, Yang Xie, Michael Miller, Fenna M. Krienen, Qiangge Zhang, Naz Taskin, Jonathan Ting, Guoping Feng, Steven A. McCarroll, Edward M. Callaway, Ting Wang, Ed S. Lein, M. Margarita Behrens, Joseph R. Ecker () and Bing Ren ()
Additional contact information
Nathan R. Zemke: University of California, San Diego School of Medicine
Ethan J. Armand: University of California, San Diego School of Medicine
Wenliang Wang: The Salk Institute for Biological Studies
Seoyeon Lee: University of California, San Diego School of Medicine
Jingtian Zhou: University of California, San Diego
Yang Eric Li: University of California, San Diego School of Medicine
Hanqing Liu: The Salk Institute for Biological Studies
Wei Tian: The Salk Institute for Biological Studies
Joseph R. Nery: The Salk Institute for Biological Studies
Rosa G. Castanon: The Salk Institute for Biological Studies
Anna Bartlett: The Salk Institute for Biological Studies
Julia K. Osteen: The Salk Institute for Biological Studies
Daofeng Li: Washington University School of Medicine
Xiaoyu Zhuo: Washington University School of Medicine
Vincent Xu: Washington University School of Medicine
Lei Chang: University of California, San Diego School of Medicine
Keyi Dong: University of California, San Diego School of Medicine
Hannah S. Indralingam: University of California, San Diego School of Medicine
Jonathan A. Rink: The Salk Institute for Biological Studies
Yang Xie: University of California, San Diego School of Medicine
Michael Miller: University of California, San Diego School of Medicine
Fenna M. Krienen: Princeton University
Qiangge Zhang: Broad Institute of MIT and Harvard
Naz Taskin: Allen Institute for Brain Science
Jonathan Ting: Allen Institute for Brain Science
Guoping Feng: Broad Institute of MIT and Harvard
Steven A. McCarroll: Harvard Medical School
Edward M. Callaway: The Salk Institute for Biological Studies
Ting Wang: Washington University School of Medicine
Ed S. Lein: Allen Institute for Brain Science
M. Margarita Behrens: The Salk Institute for Biological Studies
Joseph R. Ecker: The Salk Institute for Biological Studies
Bing Ren: University of California, San Diego School of Medicine

Nature, 2023, vol. 624, issue 7991, 390-402

Abstract: Abstract Divergence of cis-regulatory elements drives species-specific traits1, 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.

Date: 2023
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DOI: 10.1038/s41586-023-06819-6

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