Diametrically opposite methylome-transcriptome relationships in high-and low-CpG promoter genes in postmitotic neural rat tissue

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 -6,000 bp to -2,000 bp, p < 10^-73 for -2,000 bp to +2,000 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.