While friendly customer service and helpful views in article comments sections may once have been ubiquitous occurrences, they now, unfortunately, seem to be the exception rather than the rule. This trend extends to some of our favorite epigenetic topics, where a team led by Anne C. Ferguson-Smith (University of Cambridge, United Kingdom) now provides paradigm-breaking proof that intergenerational epigenetics effects on retrotransposon DNA methylation states in mice represent a rare event, being the exception rather than the rule.
The paradigm-shifting team initially sought to dissect the mechanisms controlling intergenerational epigenetic effects by seeking out regions in the mouse genome that bore similarities to two of the best-characterized paradigms of intergenerational epigenetic effects – the murine Agouti viable yellow and Axin Fused loci. At these loci, differing levels of DNA methylation at a promoter of an inserted intracisternal A particle (IAP) endogenous retrovirus influence gene expression and affect phenotype. While methylation status of the Agouti viable yellow and Axin Fused loci remain consistent in an individual mouse, individual mice display variably-methylated IAPs (VM-IAPs), altered gene expression and, hence, variable phenotypes (coat color and tail morphology, respectively).
In an attempt to enumerate VM-IAPs, to discover the extent of phenotype modulation by VM-IAPs, and to study the mechanisms behind intergenerational epigenetic effects, the authors employed whole-genome bisulfite sequencing (WGBS) and RNA sequencing (RNA-seq) analysis of non-cycling populations of ex vivo purified naive B and T cells from C57BL/6J mice, the most widely used inbred mouse strain.
Here’s what they found:
- The vast majority of IAPs in the mouse genome display full and stable DNA methylation with no influence on gene expression
- Although, the highly stringent systematic genome-wide screen employed by the authors identified around 100 candidate VM-IAPs with epigenetic properties similar to the Agouti viable yellow/Axin Fused loci
- The VM-IAPs exhibit stable methylation status in an individual mouse; however, the methylation state varies between individual mice
- VM-IAPs only rarely act as promoters that control the expression of adjacent genes, where promoter activity at these regions is another exception rather than the rule
- The methylation state of VM-IAPs displays locus-specificity within an individual, with flanking regions enriched for binding sites for the genomic insulator CTCF (which is methylation-sensitive and prefers unmethylated DNA)
- Interestingly, following reprogramming after fertilization, the authors discovered that VM-IAPs re-establish as variable loci in the next generation
- The authors established that intergenerational effects at these regions are a rare event
“One might have assumed that all the variably-methylated elements we identified would show memory of parental epigenetic state, as is observed for coat colour in Agouti Viable Yellow mice,” says Tessa Bertozzi, one of the study’s first authors. “There’s been a lot of excitement and hype surrounding the extent to which our epigenetic information is passed on to subsequent generations, but our work suggests that it’s not as pervasive as was previously thought.”
“In fact, what we showed was that methylation marks at these transposable elements are reprogrammed from one generation to the next,” adds Professor Ferguson-Smith. “There’s a mechanism that removes methylation from the vast majority of the genome and puts it back on again, once in the process of generating eggs and sperms and again before the fertilised egg implants into the uterus. How the methylation patterns at the regions we have identified get reconstructed after this genome-wide erasure is still somewhat of a mystery.
“We know there are some genes – imprinted genes for example– that do not get reprogrammed in this way in the early embryo. But these are exceptions, not the rule.”
For more on this paradigm-shifting study, head over to Cell, October 2018.