Abstract
The number of reports of paternal epigenetic influences on the phenotype of offspring in rodents is increasing but the molecular events involved remain unclear. Here, we show that haploinsufficiency for the histone 3 lysine 9 methyltransferase Setdb1 in the sire can influence the coat colour phenotype of wild type offspring. This effect occurs when the allele that directly drives coat colour is inherited from the dam, inferring that the effect involves an “in trans” step. The implication of this finding is that epigenetic state of the sperm can alter the expression of genes inherited on the maternally derived chromosomes. Whole genome bisulphite sequencing revealed that Setdb1 mutant mice show DNA hypomethylation at specific classes of transposable elements in the sperm. Our results identify Setdb1 as a paternal effect gene in the mouse and suggest that epigenetic inheritance may be more likely in individuals with altered levels of epigenetic modifiers.
Highlights
Epigenetic modifications that influence gene expression patterns and thereby contribute to the phenotype of an organism are usually cleared on passage through the germline
We show that Trim[28] is required for establishment of epigenetic state at Agouti viable yellow (Avy) but haploinsufficiency of the sire has no influence on coat colour phenotype of the wild type offspring
We have recently reported the identification of a number of Modifiers of murine metastable epialleles dominant (MommeD) mouse lines[32]
Summary
Epigenetic modifications that influence gene expression patterns and thereby contribute to the phenotype of an organism are usually cleared on passage through the germline. Transgenerational epigenetic inheritance has been reported at the Agouti viable yellow (Avy) allele in the mouse[14,15]. Since this discovery, the Avy allele has been extensively used as an epigenetically sensitive reporter to investigate the contribution of genetic and environmental influences to epigenetic state both within and across generations[16,17,18,19,20,21,22,23]. We hypothesized that Setdb[1] and Trim[28] might be critical factors for establishment of epigenetic state and epigenetic inheritance at Avy. Here, we report a paternal effect as a result of reduced levels of Setdb[1] on expression of a maternally inherited Avy allele. In summary our data suggests that dosage of some epigenetic modifiers is more critical in male gametes than female gametes, providing new insights into the mechanisms underlying epigenetic inheritance in mammals
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