Evolution of DNA methylation in the human brain

• Type of Material: Article
• Authors: Hyeonsoo Jeong, Georgia Institute of Technology; Isabel Mendizabal, Georgia Institute of Technology; Stefano Berto, UT Southwestern Medical Center; Paramita Chatterjee, Georgia Institute of Technology; Thomas Layman, Georgia Institute of Technology; Noriyoshi Usui, UT Southwestern Medical Center; Kazuya Toriumi, UT Southwestern Medical Center; Connor Douglas, UT Southwestern Medical Center; Devika Singh, Georgia Institute of Technology; Iksoo Huh, Georgia Institute of Technology; Todd Preuss, Emory University; Genevieve Konopka, UT Southwestern Med Ctr; Soojin Yi, Georgia Institute of Technology
• Language: English
• Date: 2021-04-01
• Publisher: Nature Portfolio
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2021
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-021-21917-7
• Title of Journal or Parent Work: Nature Communications
• Volume: 12
• Issue: 1
• Start Page: 2021
• End Page: 2021
• Grant/Funding Information: Takeda Science Foundation to N.U.; the JSPS Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers (S2603) to S.B.,; This work was partially supported by the Asan Foundation (Biomedical Science Scholarship) to H.J.; Uehara Memorial Foundation to N.U.;; N.U., K.T., and G.K.; the James S. McDonnell Foundation 21st Century Science Initiative in Understanding Human Cognition —Scholar Award and the Jon Heighten Scholar in Autism Research at UT Southwestern to G.K.;; JSPS Grant-in-Aid for Early-Career Scientists (18K14814) to N.U. and Scientific Research (C) (18K06977) to K.T.;; National Science Foundation (SBE-131719 and EF-2021635) to S.V.Y; and the NIMH (MH103517), to T.M.P., G.K., and S.V.Y. The National Chimpanzee Brain Resource was supported by NINDS (R24NS092988).; Macaque tissue collection and archiving was supported by the NIH National Center for Research Resources (P51RR165; superseded by the Office of Research Infrastructure Programs (OD P51OD11132)) to the Yerkes National Primate Research Center.
• Keywords: Maps; Tissues; Science & Technology; Neuronal subtypes; Insights; Resolution; Gene expression; Science & Technology - Other Topics; Binding; Reveal; Annotation; Multidisciplinary Sciences; Heritability
• Research Categories: Health Sciences, Pharmacology; Health Sciences, Nursing; Biology, Neuroscience; Biology, Cell

Abstract

DNA methylation is a critical regulatory mechanism implicated in development, learning, memory, and disease in the human brain. Here we have elucidated DNA methylation changes during recent human brain evolution. We demonstrate dynamic evolutionary trajectories of DNA methylation in cell-type and cytosine-context specific manner. Specifically, DNA methylation in non-CG context, namely CH methylation, has increased (hypermethylation) in neuronal gene bodies during human brain evolution, contributing to human-specific down-regulation of genes and co-expression modules. The effects of CH hypermethylation is particularly pronounced in early development and neuronal subtypes. In contrast, DNA methylation in CG context shows pronounced reduction (hypomethylation) in human brains, notably in cis-regulatory regions, leading to upregulation of downstream genes. We show that the majority of differential CG methylation between neurons and oligodendrocytes originated before the divergence of hominoids and catarrhine monkeys, and harbors strong signal for genetic risk for schizophrenia. Remarkably, a substantial portion of differential CG methylation between neurons and oligodendrocytes emerged in the human lineage since the divergence from the chimpanzee lineage and carries significant genetic risk for schizophrenia. Therefore, recent epigenetic evolution of human cortex has shaped the cellular regulatory landscape and contributed to the increased vulnerability to neuropsychiatric diseases.