Identification, Characterization, and Heritability of Murine Metastable Epialleles: Implications for Non-genetic Inheritance

Anastasiya Kazachenka,Tessa M Bertozzi,Marcela K Sjoberg-Herrera,Nic Walker,Joseph Gardner,Richard Gunning,Elena Pahita,Sarah Adams,David Adams,Anne C Ferguson-Smith

doi:10.1016/j.cell.2018.09.043

Anastasiya Kazachenka, Tessa M Bertozzi + Show 8 more

Open Access

https://doi.org/10.1016/j.cell.2018.09.043

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Journal: Cell	Publication Date: Oct 25, 2018
Citations: 127	License type: cc-by

Affiliation: University of Cambridge, Wellcome Sanger Institute

Abstract

SummaryGenerally repressed by epigenetic mechanisms, retrotransposons represent around 40% of the murine genome. At the Agouti viable yellow (Avy) locus, an endogenous retrovirus (ERV) of the intracisternal A particle (IAP) class retrotransposed upstream of the agouti coat-color locus, providing an alternative promoter that is variably DNA methylated in genetically identical individuals. This results in variable expressivity of coat color that is inherited transgenerationally. Here, a systematic genome-wide screen identifies multiple C57BL/6J murine IAPs with Avy epigenetic properties. Each exhibits a stable methylation state within an individual but varies between individuals. Only in rare instances do they act as promoters controlling adjacent gene expression. Their methylation state is locus-specific within an individual, and their flanking regions are enriched for CTCF. Variably methylated IAPs are reprogrammed after fertilization and re-established as variable loci in the next generation, indicating reconstruction of metastable epigenetic states and challenging the generalizability of non-genetic inheritance at these regions.

Highlights

Most interindividual phenotypic variation is explained by genetic variation
The first step utilized a catalog of polymorphic intracisternal A particle (IAP) ‘‘private’’ to C57BL/6J compared to CAST/EiJ mice and screened for C57BL/6J-specific IAPs potentially impacting the expression of neighboring genes
The second step used the set of identified variably methylated IAPs (VM-IAPs) candidates from the first step to develop an algorithm to identify VM-IAPs genome-wide, which was applied to all IAPs in the C57BL/6J genome regardless of impact on adjacent expression

Summary

Introduction

Most interindividual phenotypic variation is explained by genetic variation. studies in plant and animal models indicate that non-genetic mechanisms can contribute to phenotypic variability, and such phenotypes can be inherited over multiple generations (Cubas et al, 1999; Morgan and Whitelaw, 2008; Becker and Weigel, 2012). Epigenetic changes in the absence of genetic effects have been reported to have long-lasting phenotypic outcomes over multiple generations in non-mammalian organisms In mammals, such non-genetic effects are difficult to explain mechanistically, and it has been challenging to define the regulatory processes underlying the observed phenomena (Miska and Ferguson-Smith, 2016). Two of the best-characterized paradigms of non-genetic inheritance in mammals occur at the murine Agouti viable yellow (Avy) and Axin Fused (AxinFu) loci (Dickies, 1962; Vasicek et al, 1997) In these naturally occurring mutant mice, genetically identical individuals exhibit quantifiable phenotypic variability in coat color or tail morphology due to the insertion of an endogenous retrovirus (ERV) of the intracisternal A particle (IAP) class into the Agouti or the Fused loci, respectively. These studies suggest that ERVs of the IAP subclass have the potential to be variably methylated, here referred to as variably methylated IAPs (VM-IAPs)

Results

Discussion

Conclusion