RT Journal Article
SR Electronic
T1 Evolution of regulatory signatures in primate cortical neurons at cell type resolution
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.07.24.219881
DO 10.1101/2020.07.24.219881
A1 Alexey Kozlenkov
A1 Marit W. Vermunt
A1 Pasha Apontes
A1 Junhao Li
A1 Ke Hao
A1 Chet C. Sherwood
A1 Patrick R. Hof
A1 John J. Ely
A1 Michael Wegner
A1 Eran A. Mukamel
A1 Menno P. Creyghton
A1 Eugene V. Koonin
A1 Stella Dracheva
YR 2020
UL http://biorxiv.org/content/early/2020/07/27/2020.07.24.219881.abstract
AB The human cerebral cortex contains many cell types that likely underwent independent functional changes during evolution. However, cell type-specific regulatory landscapes in the cortex remain largely unexplored. Here we report epigenomic and transcriptomic analyses of the two main cortical neuronal subtypes, glutamatergic projection neurons and GABAergic interneurons, in human, chimpanzee and rhesus macaque. Using genome-wide profiling of the H3K27ac histone modification, we identify neuron-subtype-specific regulatory elements that previously went undetected in bulk brain tissue samples. Human-specific regulatory changes are uncovered in multiple genes, including those associated with language, autism spectrum disorder and drug addiction. We observe preferential evolutionary divergence in neuron-subtype-specific regulatory elements and show that a substantial fraction of pan-neuronal regulatory elements undergo subtype-specific evolutionary changes. This study sheds light on the interplay between regulatory evolution and cell-type-dependent gene expression programs, and provides a resource for further exploration of human brain evolution and function.SIGNIFICANCE The cerebral cortex of the human brain is a highly complex, heterogeneous tissue that contains many cell types which are exquisitely regulated at the level of gene expression by non-coding regulatory elements, presumably, in a cell-type-dependent manner. However, assessing the regulatory elements in individual cell types is technically challenging, and therefore, most of the previous studies on gene regulation were performed with bulk brain tissue. Here we analyze two major types of neurons isolated from the cerebral cortex of humans, chimpanzees and rhesus macaques, and report complex patterns of cell-type-specific evolution of the regulatory elements in numerous genes. Many genes with evolving regulation are implicated in language abilities as well as psychiatric disorders.Competing Interest StatementThe authors have declared no competing interest.