Functional annotation of the human brain methylome identifies tissue-specific epigenetic variation across brain and blood

BackgroundDynamic changes to the epigenome play a critical role in establishing and maintaining cellular phenotype during differentiation, but little is known about the normal methylomic differences that occur between functionally distinct areas of the brain. We characterized intra- and inter-individual methylomic variation across whole blood and multiple regions of the brain from multiple donors.ResultsDistinct tissue-specific patterns of DNA methylation were identified, with a highly significant over-representation of tissue-specific differentially methylated regions (TS-DMRs) observed at intragenic CpG islands and low CG density promoters. A large proportion of TS-DMRs were located near genes that are differentially expressed across brain regions. TS-DMRs were significantly enriched near genes involved in functional pathways related to neurodevelopment and neuronal differentiation, including BDNF, BMP4, CACNA1A, CACA1AF, EOMES, NGFR, NUMBL, PCDH9, SLIT1, SLITRK1 and SHANK3. Although between-tissue variation in DNA methylation was found to greatly exceed between-individual differences within any one tissue, we found that some inter-individual variation was reflected across brain and blood, indicating that peripheral tissues may have some utility in epidemiological studies of complex neurobiological phenotypes.ConclusionsThis study reinforces the importance of DNA methylation in regulating cellular phenotype across tissues, and highlights genomic patterns of epigenetic variation across functionally distinct regions of the brain, providing a resource for the epigenetics and neuroscience research communities.

[1]  P. Emson,et al.  Molecular characterization and localization of human metabotropic glutamate receptor type 3. , 1996, Brain research. Molecular brain research.

[2]  P. Emson,et al.  Molecular characterization and localization of human metabotropic glutamate receptor type 4. , 1996, Brain research. Molecular brain research.

[3]  Y. Jan,et al.  Differential expression of mammalian Numb, Numblike and Notch1 suggests distinct roles during mouse cortical neurogenesis. , 1997, Development.

[4]  M. Konishi,et al.  Brain-specific expression of a novel human UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase (GalNAc-T9). , 2000, Biochimica et biophysica acta.

[5]  K. Nave,et al.  Multiple Splice Isoforms of Proteolipid M6B in Neurons and Oligodendrocytes , 2001, Molecular and Cellular Neuroscience.

[6]  A. van Ooyen,et al.  The role of calcium signaling in early axonal and dendritic morphogenesis of rat cerebral cortex neurons under non-stimulated growth conditions. , 2001, Brain research. Developmental brain research.

[7]  R. Douglas,et al.  Na+/Ca2+ exchanger expression in the developing rat cortex , 2002, Neuroscience.

[8]  C. Goodman,et al.  Regulation of Cortical Dendrite Development by Slit-Robo Interactions , 2002, Neuron.

[9]  E. Shooter,et al.  The Neurotrophin Receptor p75NTR as a Positive Modulator of Myelination , 2002, Science.

[10]  J. Isaac,et al.  Trafficking and surface expression of the glutamate receptor subunit, KA2. , 2003, Biochemical and biophysical research communications.

[11]  E. Eichler,et al.  Regional patterns of gene expression in human and chimpanzee brains. , 2004, Genome research.

[12]  M. Pangalos,et al.  Marlin-1, a Novel RNA-binding Protein Associates with GABA Receptors* , 2004, Journal of Biological Chemistry.

[13]  S. Horvath,et al.  Statistical Applications in Genetics and Molecular Biology , 2011 .

[14]  Y. Leea,et al.  Analysis of oncogenic signaling networks in glioblastoma identifies ASPM as a molecular target , 2006 .

[15]  P. Hevezi,et al.  Gene expression analyses reveal molecular relationships among 20 regions of the human CNS , 2006, Neurogenetics.

[16]  A. Munnich,et al.  Homozygous silencing of T-box transcription factor EOMES leads to microcephaly with polymicrogyria and corpus callosum agenesis , 2007, Nature Genetics.

[17]  P. Sassone-Corsi,et al.  Signaling to the circadian clock: plasticity by chromatin remodeling. , 2007, Current opinion in cell biology.

[18]  Jonathan Pevsner,et al.  DNA methylation signatures within the human brain. , 2007, American journal of human genetics.

[19]  Michael B. Stadler,et al.  Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome , 2007, Nature Genetics.

[20]  Jun Dong,et al.  Geometric Interpretation of Gene Coexpression Network Analysis , 2008, PLoS Comput. Biol..

[21]  Steve Horvath,et al.  WGCNA: an R package for weighted correlation network analysis , 2008, BMC Bioinformatics.

[22]  Sun-Chong Wang,et al.  Epigenomic profiling reveals DNA-methylation changes associated with major psychosis. , 2008, American journal of human genetics.

[23]  A. Bird,et al.  DNA methylation landscapes: provocative insights from epigenomics , 2008, Nature Reviews Genetics.

[24]  J. Sweatt,et al.  Epigenetic Regulation of bdnf Gene Transcription in the Consolidation of Fear Memory , 2008, The Journal of Neuroscience.

[25]  E. Nestler,et al.  Histone acetylation in drug addiction. , 2009, Seminars in cell & developmental biology.

[26]  J. Buxbaum,et al.  SLITRK1 Binds 14-3-3 and Regulates Neurite Outgrowth in a Phosphorylation-Dependent Manner , 2009, Biological Psychiatry.

[27]  D. Geschwind,et al.  Functional and Evolutionary Insights into Human Brain Development through Global Transcriptome Analysis , 2009, Neuron.

[28]  Robert W. Williams,et al.  To What Extent is Blood a Reasonable Surrogate for Brain in Gene Expression Studies: Estimation from Mouse Hippocampus and Spleen , 2009, Front. Neurogen..

[29]  Martin J Aryee,et al.  Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts , 2009, Nature Genetics.

[30]  F. Coppedè,et al.  Genetics, environmental factors and the emerging role of epigenetics in neurodegenerative diseases. , 2009, Mutation research.

[31]  F. Gage,et al.  Epigenetic choreographers of neurogenesis in the adult mammalian brain , 2010, Nature Neuroscience.

[32]  Ralf Herwig,et al.  Computational analysis of genome-wide DNA methylation during the differentiation of human embryonic stem cells along the endodermal lineage. , 2010, Genome research.

[33]  R. Plomin,et al.  Allelic skewing of DNA methylation is widespread across the genome. , 2010, American journal of human genetics.

[34]  S. Han,et al.  The expression of non-clustered protocadherins in adult rat hippocampal formation and the connecting brain regions , 2010, Neuroscience.

[35]  S. Tsuji,et al.  Mapping of autosomal dominant cerebellar ataxia without the pathogenic PPP2R2B mutation to the locus for spinocerebellar ataxia 12. , 2010, Archives of neurology.

[36]  Michael Weber,et al.  Targets and dynamics of promoter DNA methylation during early mouse development , 2010, Nature Genetics.

[37]  T. Mikkelsen,et al.  The NIH Roadmap Epigenomics Mapping Consortium , 2010, Nature Biotechnology.

[38]  Arturas Petronis,et al.  Epigenetics as a unifying principle in the aetiology of complex traits and diseases , 2010, Nature.

[39]  R. Hevner,et al.  Autism susceptibility candidate 2 (Auts2) encodes a nuclear protein expressed in developing brain regions implicated in autism neuropathology. , 2010, Gene expression patterns : GEP.

[40]  Allen D. Delaney,et al.  Conserved Role of Intragenic DNA Methylation in Regulating Alternative Promoters , 2010, Nature.

[41]  Madeleine P. Ball,et al.  Neuronal activity modifies DNA methylation landscape in the adult brain , 2011, Nature Neuroscience.

[42]  D. Balding,et al.  Epigenome-wide association studies for common human diseases , 2011, Nature Reviews Genetics.

[43]  M. Herbert,et al.  SHANK3, the synapse, and autism. , 2011, The New England journal of medicine.

[44]  Rodney C. Samaco,et al.  Complexities of Rett Syndrome and MeCP2 , 2011, The Journal of Neuroscience.

[45]  Austin G Smith,et al.  Interplay between FGF2 and BMP controls the self-renewal, dormancy and differentiation of rat neural stem cells , 2011, Journal of Cell Science.

[46]  Robert S. Illingworth,et al.  Cell type-specific DNA methylation at intragenic CpG islands in the immune system. , 2011, Genome research.

[47]  K. Lesch,et al.  Epigenetic regulation of the BDNF gene: implications for psychiatric disorders , 2012, Molecular Psychiatry.