Reduced PRC2 function alters male germline epigenetic programming and paternal inheritance

Jessica M Stringer,Jessica M Stringer,David K Gardner,Moira K O'Bryan,Samuel C Forster,Samuel C Forster,Samuel C Forster,David Adelson,Lexie Prokopuk,Lexie Prokopuk,Zhipeng Qu,Patrick S Western,Patrick S Western,Stefan J White

doi:10.1186/s12915-018-0569-5

Abstract

BackgroundDefining the mechanisms that establish and regulate the transmission of epigenetic information from parent to offspring is critical for understanding disease heredity. Currently, the molecular pathways that regulate epigenetic information in the germline and its transmission to offspring are poorly understood.ResultsHere we provide evidence that Polycomb Repressive Complex 2 (PRC2) regulates paternal inheritance. Reduced PRC2 function in mice resulted in male sub-fertility and altered epigenetic and transcriptional control of retrotransposed elements in foetal male germ cells. Males with reduced PRC2 function produced offspring that over-expressed retrotransposed pseudogenes and had altered preimplantation embryo cleavage rates and cell cycle control.ConclusionThis study reveals a novel role for the histone-modifying complex, PRC2, in paternal intergenerational transmission of epigenetic effects on offspring, with important implications for understanding disease inheritance.

Highlights

Defining the mechanisms that establish and regulate the transmission of epigenetic information from parent to offspring is critical for understanding disease heredity
Litters sired by Eedhypo/hypo males were highly variable in size, resulting in a significantly increased standard deviation compared to Eedhypo/wt and Eedwt/wt controls (Bartlett’s test p = 0.0002) (Fig. 1a)
As transgene silencing has been observed in other epigenetic models [43,44,45], we proposed that the stochastic Oct4GFP silencing in Eedhypo/hypo germ cells was indicative of an altered epigenetic state in the germline of ectoderm development (Eed) hypomorphic males

Summary

Introduction

Defining the mechanisms that establish and regulate the transmission of epigenetic information from parent to offspring is critical for understanding disease heredity. The molecular pathways that regulate epigenetic information in the germline and its transmission to offspring are poorly understood. It is well established that DNA methylation is passed through the germline (oocytes and sperm) to the following generation, where it influences gene activity, embryonic development and post-natal life [1, 3,4,5]. Recent studies have demonstrated effects of histone demethylases on inheritance [6, 7]. We provide evidence that epigenetic inheritance in mice is altered by a hypomorphic mutation in embryonic ectoderm development (Eed), a gene that is essential for H3K27 trimethylation (H3K27me3)

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