Sperm is epigenetically programmed to regulate gene transcription in embryos

Abstract

For a long time, it has been assumed that the only role of sperm at fertilization is to introduce the male genome into the egg. Recently, ideas have emerged that the epigenetic state of the sperm nucleus could influence transcription in the embryo. However, conflicting reports have challenged the existence of epigenetic marks on sperm genes, and there are no functional tests supporting the role of sperm epigenetic marking on embryonic gene expression. Here, we show that sperm is epigenetically programmed to regulate embryonic gene expression. By comparing the development of sperm- and spermatid-derived frog embryos, we show that the programming of sperm for successful development relates to its ability to regulate transcription of a set of developmentally important genes. During spermatid maturation into sperm, these genes lose H3K4me2/3 and retain H3K27me3 marks. Experimental removal of these epigenetic marks at fertilization de-regulates gene expression in the resulting embryos in a paternal chromatin-dependent manner. This demonstrates that epigenetic instructions delivered by the sperm at fertilization are required for correct regulation of gene expression in the future embryos. The epigenetic mechanisms of developmental programming revealed here are likely to relate to the mechanisms involved in transgenerational transmission of acquired traits. Understanding how parental experience can influence development of the progeny has broad potential for improving human health.

Zygotic Genome Activation in Vertebrates

“…Although most sperm DNA is compacted with protamines, some of the DNA is not—about 10–15% in humans, 5–10% in mouse, the entire zebrafish genome, and species-dependent amounts in amphibians is instead bound by paternal nucleosomes (Jung et al, 2017; Mann et al, 1982; Wu et al, 2011). This raises the possibility that stable nucleosome occupancy at particular genes could influence zygotic gene expression possibly by maintaining histone modifications at these loci (Carone et al, 2014; Hammoud et al, 2009; Jung et al, 2017; Royo et al, 2016; Teperek et al, 2016; van der Heijden et al, 2005). Some discrepancies exist among which loci are believed to retain nucleosomes, perhaps due to slight differences in experimental conditions (Saitou and Kurimoto, 2014).…”

Exposure to the widely used herbicide atrazine results in deregulation of global tissue-specific RNA transcription in the third generation and is associated with a global decrease of histone trimethylation in mice

“…The role of histones in transgenerational inheritance also was demonstrated in Caenorhabditis elegans , where H3K27me and PRC2 transmit a memory of repression across generations and during development (29). Another piece of evidence corroborating the role for histones in transgenerational inheritance came from the work that showed sperm to be epigenetically programmed to regulate the transcription of several embryonic genes (30). The disruption of histone methylation in the developing sperm impairs the health of the offspring (31).…”

Functions and mechanisms of epigenetic inheritance in animals

“…The degree of nucleosome retention in vertebrate sperm varies greatly. Whereas zebrafish retain their entire nucleosomal con tent 138 , in Xenopus laevis, only ~10% of the nucleosomes are retained in the mature sperm 139 . This level is similar to that in humans, whereas in mice the degree of nucleo some retention is close to 1% 118 .…”