Genomic properties of variably methylated retrotransposons in mouse

Abstract

Background Transposable elements (TEs) are enriched in cytosine methylation, preventing their mobility within the genome. We previously identified a genome-wide repertoire of candidate intracisternal A particle (IAP) TEs in mice that exhibit inter-individual variability in this methylation (VM-IAPs) with implications for genome function. Results Here we validate these metastable epialleles and discover a novel class that exhibit tissue specificity (tsVM-IAPs) in addition to those with uniform methylation in all tissues (constitutive- or cVM-IAPs); both types have the potential to regulate genes in cis. Screening for variable methylation at other TEs shows that this phenomenon is largely limited to IAPs, which are amongst the youngest and most active endogenous retroviruses. We identify sequences enriched within cVM-IAPs, but determine that these are not sufficient to confer epigenetic variability. CTCF is enriched at VM-IAPs with binding inversely correlated with DNA methylation. We uncover dynamic physical interactions between cVM-IAPs with low methylation ranges and other genomic loci, suggesting that VM-IAPs have the potential for long-range regulation. Conclusion Our findings indicate that a recently evolved interplay between genetic sequence, CTCF binding, and DNA methylation at young TEs can result in inter-individual variability in transcriptional outcomes with implications for phenotypic variation.

A spontaneous genetically induced epiallele at a retrotransposon shapes host genome function

“…Indeed, IAP transcripts are rarely detected in somatic tissues outside of tumours and early embryogenesis, but thymic and activated splenic cells are notable exceptions (Kuff and Lueders, 1988). In addition, young ERVs have recently been implicated in shaping the evolution of transcriptional networks underlying innate immunity (Chuong et al, 2016;Tie et al, 2018;Ye et al, 2020), and our group recently identified individual IAP elements that exhibit inter-individual methylation variability exclusively in B cells (Elmer et al, 2021).…”

“…Following our genome-wide screen for VM-IAPs in the B6 genome, DNA methylation at the distal CpGs of the 5′ LTR of each candidate was validated using genomic DNA (gDNA) extracted from adult inbred B6 mice (Elmer et al, 2021;Kazachenka et al, 2018). While VM-IAP DNA methylation levels display continuous probability distributions in the B6 population, the IAP-Pgm2 5′ LTR exhibited three distinct states: high (> 85%), low (< 20%), and intermediate (60-70%) methylation (Figure 1A and B).…”

“…We previously carried out a genome-wide screen to probe the generalisability of interindividual methylation variability at IAPs (Elmer et al, 2021;Kazachenka et al, 2018). We identified dozens of novel variably methylated IAPs (VM-IAPs) in the B6 genome and showed that their characteristic methylation variability is recapitulated from generation to generation irrespective of parental methylation level.…”

Endogenous Retroviruses (ERVs): Does RLR (RIG-I-Like Receptors)-MAVS Pathway Directly Control Senescence and Aging as a Consequence of ERV De-Repression?

“…In B and T cells of C57BL/6 J, DNA methylation levels in TEs of retroviral origin correlate inversely with CTCF binding. This indicates that there is a close relationship between DNA methylation and the regulation of chromatin status and loop formation ( 43 ) ( Figure 2 ).…”

Tissue- and ethnicity-independent hypervariable DNA methylation states show evidence of establishment in the early human embryo

“…In mice, variable methylation states have been associated with the Intracisternal A Particle (IAP) class of endogenous retrovirus 58,59 , with growing evidence that methylation variability may in part be driven by incomplete silencing of IAPs in early development [60][61][62] . In humans, SIV-CpGs are enriched for proximal endogenous retrovirus elements (ERVs) 63 , including the subclasses ERV1 and ERVK 26 .…”