Abstract
Parent-of-origin effects comprise a range of genetic and epigenetic mechanisms of inheritance. Recently, detection of such effects implicated epigenetic mechanisms in the etiology of multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system. We here sought to dissect the magnitude and the type of parent-of-origin effects in the pathogenesis of experimental neuroinflammation under controlled environmental conditions. We investigated inheritance of an MS-like disease in rat, experimental autoimmune encephalomyelitis (EAE), using a backcross strategy designed to identify the parental origin of disease-predisposing alleles. A striking 37–54% of all detected disease-predisposing loci depended on parental transmission. Additionally, the Y chromosome from the susceptible strain contributed to disease susceptibility. Accounting for parent-of-origin enabled more powerful and precise identification of novel risk factors and increased the disease variance explained by the identified factors by 2-4-fold. The majority of loci displayed an imprinting–like pattern whereby a gene expressed only from the maternal or paternal copy exerts an effect. In particular, a locus on chromosome 6 comprises a well-known cluster of imprinted genes including the paternally expressed Dlk1, an atypical Notch ligand. Disease-predisposing alleles at the locus conferred lower Dlk1 expression in rats and, together with data from transgenic overexpressing Dlk1 mice, demonstrate that reduced Dlk1 drives more severe disease and modulates adaptive immune reactions in EAE. Our findings suggest a significant epigenetic contribution to the etiology of EAE. Incorporating these effects enables more powerful and precise identification of novel risk factors with diagnostic and prognostic implications for complex disease.
Highlights
Complex diseases, like common chronic inflammatory conditions, arise from an interplay between multiple risk genes and environmental factors
Such states are mediated by DNA methylation and post-translational modifications to core histones that have an impact on gene expression [1]
Our study is the first that establishes (i) the magnitude and (ii) the type of parent-of-origin effects in the pathogenesis of a multiple sclerosis-like disease, experimental autoimmune encephalomyelitis (EAE) in rat, using a strategy designed to identify genes that confer risk only when inherited from either mother or father
Summary
Like common chronic inflammatory conditions, arise from an interplay between multiple risk genes and environmental factors. Epigenetic mechanisms might act at the interface between the genome and environmental signals and determine stable and heritable changes in gene expression that do not require changes in the DNA sequence. Such states are mediated by DNA methylation and post-translational modifications to core histones that have an impact on gene expression [1]. Monozygotic twins acquire differences in chromatin structure during their life span [4,5] Such altered epigenetic states might confer differences in disease susceptibility between monozygotic twins, as shown in systemic lupus erythematosus [6]. Some environmentally-associated epigenetic changes might even be transmitted through generations, as suggested in humans [7,8] and demonstrated in mice and rats [9,10,11]
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