GSE159110
Genomic properties of variably-methylated retrotransposons in mouse
Transposable elements (TEs) are enriched in cytosine methylation, preventing their mobility within the genome. Two examples of TEs that escape this regulation are the murine-specific intracisternal A particle (IAP) elements Avy and AxinFu, which exhibit inter-individual variability in methylation associated with phenotypic variation. To determine the frequency of this phenomenon, its underlying mechanisms, and its effects on gene expression, we previously conducted a screen identifying variably methylated IAPs (VM-IAPs). Here, we fully validate these elements, categorising VM-IAPs for the first time into those exhibiting tissue specificity (tsVM-IAPs) and those showing uniform methylation among tissues (constitutive- or cVM-IAPs) with both types having the potential to regulate the genome in cis. Using our validated set of VM-IAPs, we explore how variable methylation is established and identify sequences enriched within cVM-IAPs, implicating genetics as a determinant of variability. CTCF, a methylation-sensitive transcription factor known for its role in facilitating chromatin interactions, is enriched at VM-IAPs and we show that CTCF binding is inversely correlated with methylation at cVM-IAPs. We uncover dynamic physical interactions between lowly-methylated cVM-IAPs and other genomic loci, suggesting that VM-IAPs have the potential for long-range genomic regulation. Lastly, screening for variably methylated regions in other TEs shows that this phenomenon is largely limited to IAPs, which are amongst the youngest and most active endogenous retroviruses. We propose that a recently evolved interplay between genetic sequence, CTCF binding, and DNA methylation at young TEs has the potential to cause inter-individual variability in transcriptional outcomes with implications for phenotypic variation. Overall design: CTCF ChIP-seq of eight individual mouse livers and 4C-seq of five genomic loci across five individual mouse livers