Divergent neuronal DNA methylation patterns across human cortical development reveal critical periods and a unique role of CpH methylation
Year: 2019
Type: article
Abstract: BACKGROUND: DNA methylation (DNAm) is a critical regulator of both development and cellular identity and shows unique patterns in neurons. To better characterize maturational changes in DNAm patterns in these cells, we profile the DNAm landscape at single-base resolution across the first two decades of human neocortical development in NeuN+ neurons using whole-genome bisulfite sequencing and compare them to non-neurons (primarily glia) and prenatal homogenate cortex. RESULTS: We show that DNAm changes more dramatically during the first 5 years of postnatal life than during the entire remaining period. We further refine global patterns of increasingly divergent neuronal CpG and CpH methylation (mCpG and mCpH) into six developmental trajectories and find that in contrast to genome-wide patterns, neighboring mCpG and mCpH levels within these regions are highly correlated. We integrate paired RNA-seq data and identify putative regulation of hundreds of transcripts and their splicing events exclusively by mCpH levels, independently from mCpG levels, across this period. We finally explore the relationship between DNAm patterns and development of brain-related phenotypes and find enriched heritability for many phenotypes within identified DNAm features. CONCLUSIONS: By profiling DNAm changes in NeuN-sorted neurons over the span of human cortical development, we identify novel, dynamic regions of DNAm that would be masked in homogenate DNAm data; expand on the relationship between CpG methylation, CpH methylation, and gene expression; and find enrichment particularly for neuropsychiatric diseases in genomic regions with cell type-specific, developmentally dynamic DNAm patterns.
Source: Genome biology
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,490
Funders: Yale University, University of Southern California, State University of New York, Johns Hopkins University, Lieber Institute for Brain Development, National Institutes of Health, University of California, Los Angeles, University of California, San Francisco, State University of New York Upstate Medical University, National Institute of Mental Health
Awards: Integrative Genomics of the Corticolimbic Circuit in Major Depressive Disorder, Functional methylomics approaches for schizophrenia in the frontal cortex and hippocampus, 1/3 Integrative Genomic Analysis of Human Brain Development and Autism, Transcriptional and Epigenetic Signatures of Human Brain Development and Autism, G3021430819, Long non-coding RNAs in gene regulatory networks underlying Autism, Decomposing cell type-specific marks in post-mortem human brain studies, 1/2 Measuring translational dynamics and the proteome to identify potential brain biomakers for psychiatric disease, Gene regulatory elements and transcriptome in iPSCs and embryonic human cortex, 2/3 Integrative Genomic Analysis of Human Brain Development and Autism, Risk genetic variants and cis regulation of gene expression in Bipolar Disorder, Genetic variants affect brain gene expression and risks of psychiatric disorders, Establishing comprehensive and quantitative maps of DNA methylation in the develo, Functional Genomics of Human Brain Development, 2/2-Measuring translational dynamics and the proteome to identify potential brain biomarkers for psychiatric disease, Cis-Regulatory Epigenome Mappings in Schizophrenia, RNA Sequencing of the Limbic System in Bipolar Disorder, GABA Epigenomes in Autism, Epigenetic and Transcriptional Dysregulation in Autism Spectrum Disorder, Mapping the role of long noncoding RNAs in gene regulatory networks in schizophrenia, Characterizing the developing human brain transcriptome at single-base resolution, The USC PsychENCODE Project, 3/3 Integrative Genomic Analysis of Human Brain Development and Autism, Molecular Profiling of Schizophrenia, G9000195249
OpenAlex ID: W2977146052