CpG dinucleotide positioning patterns determine the binding affinity of methyl-binding domain to nucleosomes

The methyl-binding domain of MBD1 is a common methyl CpG binding motif and has been linked to transcriptional repression. Understanding the dynamics of MBD1 binding to nucleosomal DNA is crucial, but the molecular interactions between MBD1 and chromatin remain elusive. In this study, we found the binding of MBD1 to nucleosomes demonstrates sequence preferences depending on the position of the methyl groups on the nucleosome. Specifically, binding was favored at meCpG sites in the dyad proximal region and facing towards the histone octamers. At locations where the meCpG sites face away from the histone octamer, the binding affinity was significantly lower. Interestingly, the binding of ΔMBD1 at methylated CpG sites facing away from histone octamers induces conformational changes of nucleosomes, resulting in a more “open” conformation. The biological implication of DNA methylation is thus likely to be synergistically regulated via DNA sequences contents and their nucleosome-positioning patterns based on our in vitro findings.