How Can CpG Methylations, and Pair-to-Pair Correlations between the Main (Gene) and the Opposite Strands, Suggest a Bending DNA Loop: Insights into the 5′-UTR of DAT1

Abstract

A working hypothesis issues from patterns of methylation in the 5′-UTR of the DAT1 gene. We considered relationships between pairs of CpGs, of which one on the main-gene strand and another on the complementary opposite strand (COS). We elaborated on data from ADHD children: we calculated all possible combinations of probabilities (estimated by multiplying two raw values of methylation) in pairs of CpGs from either strand. We analyzed all correlations between any given pair and all other pairs. For pairs correlating with M6-M6COS, some pairs had cytosines positioning to the reciprocal right (e.g., M3-M2COS and M6-M5COS), other pairs had cytosines positioning to the reciprocal left (e.g., M2-M3COS; M5-M6COS). Significant pair-to-pair correlations emerged between main-strand and COS CpG pairs. Through graphic representations, we hypothesized that DNA folded to looping conformations: the C1GG C2GG C3GG and C5G C6G motifs would become close enough to allow cytosines 1-2-3 to interact with cytosines 5-6 (on both strands). Data further suggest a sliding, with left- and right-ward oscillations of DNA strands. While thorough empirical verification is needed, we hypothesize simultaneous methylation of main-strand and COS DNA (“methylation dynamics”) to serve as a promising biomarker.