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Genome Res. 2011 Oct;21(10):1583-91. doi: 10.1101/gr.119131.110. Epub 2011 Jul 22.

Large-scale methylation domains mark a functional subset of neuronally expressed genes.

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  • 1School of Medicine, Medical Microbiology and Immunology, University of California Davis, Davis, California 95616, USA.

Abstract

DNA methylation is essential for embryonic and neuronal differentiation, but the function of most genomic DNA methylation marks is poorly understood. Generally the human genome is highly methylated (>70%) except for CpG islands and gene promoters. However, it was recently shown that the IMR90 human fetal lung fibroblast cells have large regions of the genome with partially methylated domains (PMDs, <70% average methylation), in contrast to the rest of the genome which is in highly methylated domains (HMDs, >70% average methylation). Using bisulfite conversion followed by high-throughput sequencing (MethylC-seq), we discovered that human SH-SY5Y neuronal cells also contain PMDs. We developed a novel hidden Markov model (HMM) to computationally map the genomic locations of PMDs in both cell types and found that autosomal PMDs can be >9 Mb in length and cover 41% of the IMR90 genome and 19% of the SH-SY5Y genome. Genomic regions marked by cell line specific PMDs contain genes that are expressed in a tissue-specific manner, with PMDs being a mark of repressed transcription. Genes contained within N-HMDs (neuronal HMDs, defined as a PMD in IMR90 but HMD in SH-SY5Y) were significantly enriched for calcium signaling, synaptic transmission, and neuron differentiation functions. Autism candidate genes were enriched within PMDs and the largest PMD observed in SH-SY5Y cells marked a 10 Mb cluster of cadherin genes with strong genetic association to autism. Our results suggest that these large-scale methylation domain maps could be relevant to interpreting and directing future investigations into the elusive etiology of autism.

PMID:
21784875
[PubMed - indexed for MEDLINE]
PMCID:
PMC3202276
Free PMC Article

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