title: Genome-wide disruption of 5-hydroxymethylcytosine in a mouse model of autism.
abstract: The autism spectrum disorders (ASD) comprise a broad group of behaviorally related neurodevelopmental disorders affecting as many as 1 in 68 children. The hallmarks of ASD consist of impaired social and communication interactions, pronounced repetitive behaviors and restricted patterns of interests. Family, twin and epidemiological studies suggest a polygenetic and epistatic susceptibility model involving the interaction of many genes; however, the etiology of ASD is likely to be complex and include both epigenetic and environmental factors. 5-hydroxymethylcytosine (5hmC) is a novel environmentally sensitive DNA modification that is highly enriched in post-mitotic neurons and is associated with active transcription of neuronal genes. Here, we used an established chemical labeling and affinity purification method coupled with high-throughput sequencing technology to generate a genome-wide profile of striatal 5hmC in an autism mouse model (Cntnap2(-/-) mice) and found that at 9 weeks of age the Cntnap2(-/-) mice have a genome-wide disruption in 5hmC, primarily in genic regions and repetitive elements. Annotation of differentially hydroxymethylated regions (DhMRs) to genes revealed a significant overlap with known ASD genes (e.g. Nrxn1 and Reln) that carried an enrichment of neuronal ontological functions, including axonogenesis and neuron projection morphogenesis. Finally, sequence motif predictions identified associations with transcription factors that have a high correlation with important genes in neuronal developmental and functional pathways. Together, our data implicate a role for 5hmC-mediated epigenetic modulation in the pathogenesis of autism and represent a critical step toward understanding the genome-wide molecular consequence of the Cntnap2 mutation, which results in an autism-like phenotype.
authors.affiliation: Department of Psychiatry.
authors.forename: Ligia A
authors.initials: LA
authors.lastname: Papale
authors.affiliation: Department of Statistics, Biostatistics, and Medical Informatics and.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Psychiatry, Neuroscience training program, University of Wisconsin, Madison, WI 53719, USA.
authors.forename: Sisi
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Statistics, Biostatistics, and Medical Informatics and.
authors.forename: Kailei
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Statistics, Biostatistics, and Medical Informatics and.
authors.forename: Sündüz
authors.initials: S
authors.lastname: Keleş
authors.affiliation: Department of Psychiatry, alisch@wisc.edu.
authors.forename: Reid S
authors.initials: RS
authors.lastname: Alisch
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives; D000818:Animals; D001321:Autistic Disorder / Q000235:genetics*; D003342:Corpus Striatum / Q000378:metabolism; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D019175:DNA Methylation; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058977:Molecular Sequence Annotation; D009419:Nerve Tissue Proteins / Q000235:genetics; D000091042:Reelin Protein
chemical_list: C568163:CNTNAP2 protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; D004247:DNA; C000717128:Reln protein, mouse