title: Diametrically opposite methylome-transcriptome relationships in high- and low-CpG promoter genes in postmitotic neural rat tissue.
abstract: DNA methylation can control some CpG-poor genes but unbiased studies have not found a consistent genome-wide association with gene activity outside of CpG islands or shores possibly due to use of cell lines or limited bioinformatics analyses. We performed reduced representation bisulfite sequencing (RRBS) of rat dorsal root ganglia encompassing postmitotic primary sensory neurons (n = 5, r > 0.99; orthogonal validation p < 10(-19)). The rat genome suggested a dichotomy of genes previously reported in other mammals: low CpG content (< 3.2%) promoter (LCP) genes and high CpG content (≥ 3.2%) promoter (HCP) genes. A genome-wide integrated methylome-transcriptome analysis showed that LCP genes were markedly hypermethylated when repressed, and hypomethylated when active with a 40% difference in a broad region at the 5' of the transcription start site (p < 10(-87) for -6000 bp to -2000 bp, p < 10(-73) for -2000 bp to +2000 bp, no difference in gene body p = 0.42). HCP genes had minimal TSS-associated methylation regardless of transcription status, but gene body methylation appeared to be lost in repressed HCP genes. Therefore, diametrically opposite methylome-transcriptome associations characterize LCP and HCP genes in postmitotic neural tissue in vivo.
authors.affiliation: Mayo Clinic, Rochester, MN, USA.
authors.forename: Theresa
authors.initials: T
authors.lastname: Hartung
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.forename: Rahul
authors.initials: R
authors.lastname: Kanwar
authors.forename: Irina
authors.initials: I
authors.lastname: Khrebtukova
authors.forename: Matthias
authors.initials: M
authors.lastname: Reinhardt
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.forename: Terry M
authors.initials: TM
authors.lastname: Therneau
authors.forename: Michaela S
authors.initials: MS
authors.lastname: Banck
authors.forename: Gary P
authors.initials: GP
authors.lastname: Schroth
authors.forename: Andreas S
authors.initials: AS
authors.lastname: Beutler
mesh_terms: D000818:Animals; D018899:CpG Islands; D003596:Cytosine / Q000378:metabolism; D019175:DNA Methylation; D030561:Databases, Nucleic Acid; D005727:Ganglia, Spinal / Q000166:cytology* / Q000378:metabolism; D020869:Gene Expression Profiling; D016678:Genome; D008297:Male; D008938:Mitosis; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000166:cytology* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D024363:Transcription Initiation Site; D015533:Transcriptional Activation; D059467:Transcriptome
chemical_list: D003596:Cytosine