Sperm RNA, an "epigenetic rheostat" of gene expression?

Abstract

François Cuzin Inserm, U636, F-06108, Nice, France and Université de NiceSophia Antipolis, Laboratoire de Génétique du Développement Normal et Pathologique, Nice, France The question addressed in the title is raised from the observations of two groups. The presence of RNA in human spermatozoa [reviewed by Ostermeier et al. 2004; Krawetz 2005; Miller et al. 2005] and the observation of paramutation in an animal model [Rassoulzadegan et al. 2006] led us to conclude that the hereditary transmission of this epigenetic modification is associated with the transfer of RNA molecules accumulated in the sperm head. The tantalizing question is whether paramutation occurs in humans. It is, however, only in the animal model that it is possible to examine this epigenetic determination. The same genetic analysis is not possible in human since unambiguous identification of subtle modifications of gene expression requires a homogenous genetic background and serial crosses between siblings. Failing these requirements, multiple explanations are always possible for apparently non Mendelian inheritance. However, once the phenomenon has been recognized in the animal model, then consequences and correlates can be searched in the normal and pathological human conditions. To that purpose, results and hypotheses generated by the mouse studies have to be made available to the extremely difficult task of analyzing the scarce clinical genetic data. The possible function of sperm RNA in humans remains highly speculative. Analysis of paramutation in the mouse provides a new frame for hypotheses on its possible role in hereditary transmission and thus a role for sperm RNA. Excellent reviews on paramutation in plants are available [reviewed by Chandler and Stam 2004], including a comparison of plant and mouse [Chandler 2007]. The aim of this summary is to propose to the reader a working hypothesis on the possibility of gene controls exerted by RNA transferred from sperm to the embryo. History of spermatozoal RNA starts with the pioneer work performed on human sperm [reviewed in Krawetz 2005]. Its possible role(s) remain a matter of speculation [reviewed by Ostermeier et al. 2004; Miller et al. 2005]. However we have recently reported the hereditary transmission of an epigenetic change in expression of the mouse Kit gene [Rassoulzadegan et al. 2006]. Hereditary epigenetic variation was observed in plants by Brink in 1956 and has since been extensively studied as paramutation. In the mouse, the initial observation was a dramatic departure from the expected Mendelian distribution in the progeny of crosses between heterozygotes carrying the wild type Kit allele and the null allele Kit . Most of the progeny genotyped as wild type Kitþ=þ homozygotes derived from crosses between Kit tm1Alf=þ while heterozygotes maintained a large degree of variation. Received 09 March 2007; accepted 29 May 2007.