About this item:

84 Views | 80 Downloads

Author Notes:

Correspondence: Genevieve Konopka, genevieve.konopka@utsouthwestern.edu

Author contributions: Conceptualization and funding—T.M.P., G.K., and S.V.Y.; sample acquisition and dissection—G.K., T.M.P., and S.V.Y.; nuclei sorting—N.U., K.T., and C.D.; WGBS, WGS data generation: P.C., and T.L.; data curation and bioinformatics assistance

D.S., S.B., I.H.; bioinformatics analysis—H.J., I.M., G.K., and S.V.Y.; drafting—H.J., I.M., and S.V.Y.; writing—H.J., I.M., G.K., T.M.P., and S.V.Y.

Disclosures: The authors declare no competing interests.

Subjects:

Research Funding:

This work was partially supported by the Asan Foundation (Biomedical Science Scholarship) to H.J.; Uehara Memorial Foundation to N.U.;

JSPS Grant-in-Aid for Early-Career Scientists (18K14814) to N.U. and Scientific Research (C) (18K06977) to K.T.;

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.,

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.;

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Macaque tissue collection and archiving was supported by the NIH National Center for Research Resources (P51RR165; superseded by the Office of Research Infrastructure Programs (OD P51OD11132)) to the Yerkes National Primate Research Center.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:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • Gene expression
  • Neuronal subtypes
  • Maps
  • Heritability
  • Annotation
  • Resolution
  • Insights
  • Binding
  • Tissues
  • Reveal

Evolution of DNA methylation in the human brain

Show all authors Show less authors

Journal Title:

Nature Communications

Volume:

Volume 12, Number 1

Publisher:

, Pages 2021-2021

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© The Author(s) 2021

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/rdf).
Export to EndNote