Epigenetic signatures of autism: trimethylated H3K4 landscapes in prefrontal neurons.

CONTEXT Neuronal dysfunction in cerebral cortex and other brain regions could contribute to the cognitive and behavioral defects in autism. OBJECTIVE To characterize epigenetic signatures of autism in prefrontal cortex neurons. DESIGN We performed fluorescence-activated sorting and separation of neuronal and nonneuronal nuclei from postmortem prefrontal cortex, digested the chromatin with micrococcal nuclease, and deeply sequenced the DNA from the mononucleosomes with trimethylated H3K4 (H3K4me3), a histone mark associated with transcriptional regulation. Approximately 15 billion base pairs of H3K4me3-enriched sequences were collected from 32 brains. SETTING Academic medical center. PARTICIPANTS A total of 16 subjects diagnosed as having autism and 16 control subjects ranging in age from 0.5 to 70 years. MAIN OUTCOME MEASURES Identification of genomic loci showing autism-associated H3K4me3 changes in prefrontal cortex neurons. RESULTS Subjects with autism showed no evidence for generalized disruption of the developmentally regulated remodeling of the H3K4me3 landscape that defines normal prefrontal cortex neurons in early infancy. However, excess spreading of H3K4me3 from the transcription start sites into downstream gene bodies and upstream promoters was observed specifically in neuronal chromatin from 4 of 16 autism cases but not in controls. Variable subsets of autism cases exhibit altered H3K4me3 peaks at numerous genes regulating neuronal connectivity, social behaviors, and cognition, often in conjunction with altered expression of the corresponding transcripts. Autism-associated H3K4me3 peaks were significantly enriched in genes and loci implicated in neurodevelopmental diseases. CONCLUSIONS Prefrontal cortex neurons from subjects with autism show changes in chromatin structures at hundreds of loci genome-wide, revealing considerable overlap between genetic and epigenetic risk maps of developmental brain disorders.

[1]  P. Patterson,et al.  Maternal infection and immune involvement in autism. , 2011, Trends in molecular medicine.

[2]  A. Scheuerle,et al.  PARK2 copy number aberrations in two children presenting with autism spectrum disorder: Further support of an association and possible evidence for a new microdeletion/microduplication syndrome , 2011, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[3]  S. Horvath,et al.  Transcriptomic Analysis of Autistic Brain Reveals Convergent Molecular Pathology , 2011, Nature.

[4]  D. Pinto,et al.  A genotype resource for postmortem brain samples from the Autism Tissue Program , 2011, Autism research : official journal of the International Society for Autism Research.

[5]  H. Barbas,et al.  Changes in Prefrontal Axons May Disrupt the Network in Autism , 2010, The Journal of Neuroscience.

[6]  C. Lord,et al.  The Simons Simplex Collection: A Resource for Identification of Autism Genetic Risk Factors , 2010, Neuron.

[7]  Craig Newschaffer,et al.  Parent-Of-Origin Effects in Autism Identified through Genome-Wide Linkage Analysis of 16,000 SNPs , 2010, PloS one.

[8]  E. Susser,et al.  Early Life Programming and Neurodevelopmental Disorders , 2010, Biological Psychiatry.

[9]  E. Courchesne,et al.  Microglial Activation and Increased Microglial Density Observed in the Dorsolateral Prefrontal Cortex in Autism , 2010, Biological Psychiatry.

[10]  Stephen R. Williams,et al.  Haploinsufficiency of HDAC4 causes brachydactyly mental retardation syndrome, with brachydactyly type E, developmental delays, and behavioral problems. , 2010, American journal of human genetics.

[11]  S. Buyske,et al.  The Neuropeptide VGF Is Reduced in Human Bipolar Postmortem Brain and Contributes to Some of the Behavioral and Molecular Effects of Lithium , 2010, The Journal of Neuroscience.

[12]  Z. Weng,et al.  A simple method for improving the specificity of anti-methyl histone antibodies , 2010, Epigenetics.

[13]  J. Gilbert,et al.  Novel variants identified in methyl-CpG-binding domain genes in autistic individuals , 2010, neurogenetics.

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

[15]  Z. Weng,et al.  Developmental regulation and individual differences of neuronal H3K4me3 epigenomes in the prefrontal cortex , 2010, Proceedings of the National Academy of Sciences.

[16]  D J Porteous,et al.  RETHINKING THE GENETIC ARCHITECTURE OF SCHIZOPHRENIA , 2010, Schizophrenia Research.

[17]  Yoichi Shinkai,et al.  Reduced exploration, increased anxiety, and altered social behavior: Autistic-like features of euchromatin histone methyltransferase 1 heterozygous knockout mice , 2010, Behavioural Brain Research.

[18]  D. Molfese,et al.  Histone Methylation Regulates Memory Formation , 2010, The Journal of Neuroscience.

[19]  Alan R. Mardinly,et al.  The Angelman Syndrome Protein Ube3A Regulates Synapse Development by Ubiquitinating Arc , 2010, Cell.

[20]  J. Lieberman,et al.  Association of the orphan nuclear receptor NR4A1 with tardive dyskinesia , 2010, Psychiatric genetics.

[21]  R. Uher,et al.  The role of genetic variation in the causation of mental illness: an evolution-informed framework , 2009, Molecular Psychiatry.

[22]  Xinzhi Zhao,et al.  Positive association between ALDH1A2 and schizophrenia in the Chinese population , 2009, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[23]  Z. Marinova,et al.  Valproic acid induces functional heat‐shock protein 70 via Class I histone deacetylase inhibition in cortical neurons: a potential role of Sp1 acetylation , 2009, Journal of neurochemistry.

[24]  D. Arking,et al.  A GENOME-WIDE LINKAGE AND ASSOCIATION SCAN REVEALS NOVEL LOCI FOR AUTISM , 2009, Nature.

[25]  G. Turecki,et al.  Histone methylation and decreased expression of TrkB.T1 in orbital frontal cortex of suicide completers , 2009, Molecular Psychiatry.

[26]  Kazuya Iwamoto,et al.  Epigenetic Profiling in Schizophrenia and Major Mental Disorders , 2009, Neuropsychobiology.

[27]  T. Kemper,et al.  The anterior cingulate cortex in autism: heterogeneity of qualitative and quantitative cytoarchitectonic features suggests possible subgroups , 2009, Acta Neuropathologica.

[28]  Ravinesh A. Kumar,et al.  A de novo 1p34.2 microdeletion identifies the synaptic vesicle gene RIMS3 as a novel candidate for autism , 2009, Journal of Medical Genetics.

[29]  Robert T. Schultz,et al.  Autism genome-wide copy number variation reveals ubiquitin and neuronal genes , 2009, Nature.

[30]  E. Eichler,et al.  Linkage Disequilibrium between Two High-Frequency Deletion Polymorphisms: Implications for Association Studies Involving the glutathione-S transferase (GST) Genes , 2009, PLoS genetics.

[31]  Manuel Corpas,et al.  DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. , 2009, American journal of human genetics.

[32]  A. Guidotti,et al.  From trans-methylation to cytosine methylation: Evolution of the methylation hypothesis of schizophrenia , 2009, Epigenetics.

[33]  J. García-Verdugo,et al.  Chromatin remodelling factor Mll1 is essential for neurogenesis from postnatal neural stem cells , 2009, Nature.

[34]  D. Geschwind.  Advances in autism. , 2009, Annual review of medicine.

[35]  S. Akbarian,et al.  Epigenetic Regulation in Human Brain—Focus on Histone Lysine Methylation , 2009, Biological Psychiatry.

[36]  L. Shaffer,et al.  Prenatal diagnosis of monosomy 1p36: A focus on brain abnormalities and a review of the literature , 2008, American journal of medical genetics. Part A.

[37]  Clifford A. Meyer,et al.  Model-based Analysis of ChIP-Seq (MACS) , 2008, Genome Biology.

[38]  A. Guidotti,et al.  Clozapine and sulpiride but not haloperidol or olanzapine activate brain DNA demethylation , 2008, Proceedings of the National Academy of Sciences.

[39]  A. Shilatifard.  Molecular implementation and physiological roles for histone H3 lysine 4 (H3K4) methylation. , 2008, Current opinion in cell biology.

[40]  S. Scherer,et al.  Duplication of 17(p11.2p11.2) in a male child with autism and severe language delay , 2008, American journal of medical genetics. Part A.

[41]  Hanlin Gao,et al.  A novel mutation in JARID1C/SMCX in a patient with autism spectrum disorder (ASD) , 2008, American journal of medical genetics. Part A.

[42]  C. Romano,et al.  Further Delineation of Deletion 1p36 Syndrome in 60 Patients: A Recognizable Phenotype and Common Cause of Developmental Delay and Mental Retardation , 2008, Pediatrics.

[43]  Stephen P. Baker,et al.  Prefrontal Dysfunction in Schizophrenia Involves Mixed-Lineage Leukemia 1-Regulated Histone Methylation at GABAergic Gene Promoters , 2007, The Journal of Neuroscience.

[44]  A. Morton,et al.  Complexin 1 knockout mice exhibit marked deficits in social behaviours but appear to be cognitively normal. , 2007, Human molecular genetics.

[45]  Stephen T Warren,et al.  Genome-wide expression profiling of lymphoblastoid cell lines distinguishes different forms of autism and reveals shared pathways. , 2007, Human molecular genetics.

[46]  R. Jaenisch,et al.  A Chromatin Landmark and Transcription Initiation at Most Promoters in Human Cells , 2007, Cell.

[47]  Dustin E. Schones,et al.  High-Resolution Profiling of Histone Methylations in the Human Genome , 2007, Cell.

[48]  K. Devriendt,et al.  Identification and characterization of the TRIP8 and REEP3 genes on chromosome 10q21.3 as novel candidate genes for autism , 2007, European Journal of Human Genetics.

[49]  Lorraine Potocki,et al.  Characterization of Potocki-Lupski syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage-sensitive critical interval that can convey an autism phenotype. , 2007, American journal of human genetics.

[50]  S. Korsmeyer,et al.  Developmental Regulation of Eed Complex Composition Governs a Switch in Global Histone Modification in Brain* , 2007, Journal of Biological Chemistry.

[51]  J. Buxbaum,et al.  Association analysis of the NrCAM gene in autism and in subsets of families with severe obsessive–compulsive or self-stimulatory behaviors , 2006, Psychiatric genetics.

[52]  C. Gillberg,et al.  Constitutional Downregulation of SEMA5A Expression in Autism , 2006, Neuropsychobiology.

[53]  N. C. Schanen,et al.  Epigenetics of autism spectrum disorders. , 2006, Human molecular genetics.

[54]  J. LaSalle,et al.  Dynamic Changes in Histone H3 Lysine 9 Acetylation Localization Patterns During Neuronal Maturation Require MeCP2 , 2006, Epigenetics.

[55]  A. Shilatifard,et al.  Recruitment of MLL by HMG-domain protein iBRAF promotes neural differentiation , 2005, Nature Cell Biology.

[56]  M. Momoi,et al.  Mutation analysis of methyl-CpG binding protein family genes in autistic patients , 2005, Brain and Development.

[57]  E. Jones,et al.  Histone methylation at gene promoters is associated with developmental regulation and region‐specific expression of ionotropic and metabotropic glutamate receptors in human brain , 2005, Journal of neurochemistry.

[58]  Rodney Cotterill,et al.  Mutation screening and association analysis of six candidate genes for autism on chromosome 7q , 2005, European Journal of Human Genetics.

[59]  A. Zimmerman,et al.  Neuroglial activation and neuroinflammation in the brain of patients with autism , 2005, Annals of neurology.

[60]  K. Becker,et al.  The Genetic Association Database , 2004, Nature Genetics.

[61]  Manuel F. Casanova,et al.  Clinical and Macroscopic Correlates of Minicolumnar Pathology in Autism , 2002, Journal of child neurology.

[62]  S. Scherer,et al.  Disruption of a novel gene (IMMP2L) by a breakpoint in 7q31 associated with Tourette syndrome. , 2001, American journal of human genetics.

[63]  L. Luo,et al.  Cell-Autonomous Requirement of the USP/EcR-B Ecdysone Receptor for Mushroom Body Neuronal Remodeling in Drosophila , 2000, Neuron.

[64]  Jahnvi Pflueger,et al.  Distinctive chromatin in human sperm packages genes for embryo development , 2009 .