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Divergent neuronal DNA methylation patterns across human cortical development: Critical periods and a unique role of CpH methylation

AJ Price, View ORCID ProfileL Collado-Torres, NA Ivanov, W Xia, EE Burke, JH Shin, R Tao, L Ma, Y Jia, TM Hyde, JE Kleinman, DR Weinberger, View ORCID ProfileAE Jaffe
doi: https://doi.org/10.1101/428391
AJ Price
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA
2McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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L Collado-Torres
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA
3Center for Computational Biology, Johns Hopkins University, Baltimore, MD, USA
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  • ORCID record for L Collado-Torres
NA Ivanov
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA
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W Xia
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA
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EE Burke
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA
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JH Shin
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA
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R Tao
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA
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L Ma
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA
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Y Jia
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA
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TM Hyde
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA
4Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA
5Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD, USA
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JE Kleinman
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA
5Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD, USA
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DR Weinberger
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA
2McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
4Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA
5Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD, USA
6Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA
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AE Jaffe
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA
2McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
3Center for Computational Biology, Johns Hopkins University, Baltimore, MD, USA
7Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
8Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
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  • ORCID record for AE Jaffe
  • For correspondence: andrew.jaffe@libd.org
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Abstract

We characterized the landscape of DNA methylation (DNAm) across the first two decades of human neocortical development in neurons and glia using whole-genome bisulfite sequencing. We show that the rate of DNAm changes more dramatically during the first five years of postnatal life than during the entire remaining period. We further refined global patterns of increasingly divergent neuronal CpG and CpH methylation (mCpG and mCpH) into six unique developmental trajectories, within which neighboring mC levels—independent of sequence context—were highly correlated, unlike across the genome, where mCpG levels were correlated but mCpH levels were not. We then integrated paired RNA-seq data and identified direct regulation of hundreds of transcripts and their splicing events exclusively by mCpH, independent of mCpG levels, across this period of human cortical development. In addition to expanding the relationship between mCpH and gene expression, these splicing-associated cytosines and developmentally dynamic DNAm regions were associated with neuropsychiatric disease risk sequence, providing insight into the cell type and timing of dynamic epigenomic remodeling in known disease risk genes and loci.

Significance Statement By studying DNA methylation levels within neurons and glia across human neocortical development, we show that the first five years of life is a critical period of epigenetic plasticity, identify a novel role of CpH methylation in gene expression and splicing during neuronal maturation and parlay a clearer picture of methylation remodeling into better understanding of the cell type and timing of neuropsychiatric disease risk sequence activity.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted September 29, 2018.
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Divergent neuronal DNA methylation patterns across human cortical development: Critical periods and a unique role of CpH methylation
AJ Price, L Collado-Torres, NA Ivanov, W Xia, EE Burke, JH Shin, R Tao, L Ma, Y Jia, TM Hyde, JE Kleinman, DR Weinberger, AE Jaffe
bioRxiv 428391; doi: https://doi.org/10.1101/428391
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Divergent neuronal DNA methylation patterns across human cortical development: Critical periods and a unique role of CpH methylation
AJ Price, L Collado-Torres, NA Ivanov, W Xia, EE Burke, JH Shin, R Tao, L Ma, Y Jia, TM Hyde, JE Kleinman, DR Weinberger, AE Jaffe
bioRxiv 428391; doi: https://doi.org/10.1101/428391

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