Scientific Understanding of Consciousness
Consciousness as an Emergent Property of Thalamocortical Activity

Brain Development Epigenomic Reconfiguration

 

Science, 9 August 2013: Vol. 341 no. 6146, p.629

Global Epigenomic Reconfiguration During Mammalian Brain Development

Ryan Lister, Eran A. Mukame, Joseph R. Nery, Mark Urich, Clare A. Puddifoot, Nicholas D. Johnson, Jacinta Lucero, Yun Huang, Andrew J. Dwork, Matthew D. Schultz, Miao Yu, Julian Tonti-Filippini, Holger Heyn, Shijun Hu, Joseph C. Wu, Anjana Rao, Manel Esteller, Chuan He, Fatemeh G. Haghighi, Terrence J. Sejnowski, M. Margarita Behrens, Joseph R. Ecker

¹Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

²Plant Energy Biology [Australian Research Council Center of Excellence (CoE)] and Computational Systems Biology (Western Australia CoE), School of Chemistry and Biochemistry, The University of Western Australia, Perth, WA 6009, Australia.

³Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

⁴La Jolla Institute for Allergy and Immunology and Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA.

⁵Department of Psychiatry, Columbia University and The New York State Psychiatric Institute, New York, NY 10032, USA.

⁶Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.

⁷Bioinformatics Program, University of California at San Diego, La Jolla, CA 92093, USA.

⁸Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA.

⁹Cancer Epigenetics Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona 08907, Spain.

¹⁰Department of Medicine, Division of Cardiology, Stanford University School of Medicine, Stanford, CA 94305, USA.

¹¹Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.

¹²Division of Biological Sciences, University of California at San Diego, La Jolla, CA 92037, USA.

¹³Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

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Introduction

Several lines of evidence point to a key role for dynamic epigenetic changes during brain development, maturation, and learning. DNA methylation (mC) is a stable covalent modification that persists in post-mitotic cells throughout their lifetime, defining their cellular identity. However, the methylation status at each of the ~1 billion cytosines in the genome is potentially an information-rich and flexible substrate for epigenetic modification that can be altered by cellular activity. Indeed, changes in DNA methylation have been implicated in learning and memory, as well as in age-related cognitive decline. However, little is known about the cell type–specific patterning of DNA methylation and its dynamics during mammalian brain development.

Methods

We performed genome-wide single-base resolution profiling of the composition, patterning, cell specificity, and dynamics of DNA methylation in the frontal cortex of humans and mice throughout their lifespan (MethylC-Seq). Furthermore, we generated base-resolution maps of 5-hydroxymethylcytosine (hmC) in mammalian brains by TAB-Seq at key developmental stages, accompanied by RNA-Seq transcriptional profiling.

Results

Extensive methylome reconfiguration occurs during development from fetal to young adult. In this period, coincident with synaptogenesis, highly conserved non-CG methylation (mCH) accumulates in neurons, but not glia, to become the dominant form of methylation in the human neuronal genome. We uncovered surprisingly complex features of brain cell DNA methylation at multiple scales, first by identifying intragenic methylation patterns in neurons and glia that distinguish genes with cell type–specific activity. Second, we report a novel mCH signature that identifies genes escaping X-chromosome inactivation in neurons. Third, we find >100,000 developmentally dynamic and cell type–specific differentially CG-methylated regions that are enriched at putative regulatory regions of the genome. Finally, whole-genome detection of 5-hydroxymethylcytosine (hmC) at single-base resolution revealed that this mark is present in fetal brain cells at locations that lose CG methylation and become activated during development. CG-demethylation at these hmC-poised loci depends on Tet2 activity.

Discussion

Whole-genome single-base resolution methylcytosine and hydroxymethylcytosine maps revealed profound changes during frontal cortex development in humans and mice. These results extend our knowledge of the unique role of DNA methylation in brain development and function, and offer a new framework for testing the role of the epigenome in healthy function and in pathological disruptions of neural circuits. Overall, brain cell DNA methylation has unique features that are precisely conserved, yet dynamic and cell-type specific.

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