Epigenetic inheritance of acquired traits through sperm RNAs and sperm RNA modifications

Abstract

Once deemed heretical, emerging evidence now supports the notion that the inheritance of acquired characteristics can occur through ancestral exposures or experiences and that certain paternally acquired traits can be 'memorized' in the sperm as epigenetic information. The search for epigenetic factors in mammalian sperm that transmit acquired phenotypes has recently focused on RNAs and, more recently, RNA modifications. Here, we review insights that have been gained from studying sperm RNAs and RNA modifications, and their roles in influencing offspring phenotypes. We discuss the possible mechanisms by which sperm become acquisitive following environmental-somatic-germline interactions, and how they transmit paternally acquired phenotypes by shaping early embryonic development.

Figure 1. Small non-coding RNAs in mouse male germ cells

Spatiotemporal distribution of major types of small non-coding RNAs (for example, PIWI-interacting RNAs (piRNAs), microRNAs (miRNAs) and tRNA-derived small RNAs (tsRNAs)) in sperm precursors (for example, spermatogonia, spermatocyte, round spermatid and elongated spermatid) during spermatogenesis in the testis, and in spermatozoa during sperm maturation in the epididymis (which occurs during the transition from the caput epididymis to the cauda epididymis).

Figure 2. Potential mechanisms involving sperm RNAs in early embryos

a | Sperm RNA input following certain environmental exposures may trigger a transcriptional cascade in the early embryo that affects the symmetry-breaking process, and may generate phenotypes in the offspring that mirror the paternally acquired phenotypes. b | Sperm microRNAs (miRNAs) could mediate mRNA stability and/or degradation by binding to the 3′ untranslated region (UTR), which is facilitated by Argonaute (AGO), to regulate mRNA metabolism. c | Sperm tRNA-derived small RNAs (tsRNAs) showed sequence matches to gene promoters that are associated with transposable elements (TEs), with unidentified mechanisms or related binding proteins. d | Sperm long non-coding RNAs (lncRNAs) may reshape chromatin 3D structure.

Figure 3. Current knowledge of sperm RNA modifications

a | Sperm tRNA-derived small RNAs (tsRNAs) contain various RNA modifications (coloured dots) that contribute to their stability in zygote lysate; a high-fat diet (HFD) in male mice increases 5-methylcytidine (m⁵C) and N²-methylguanosine (m²G) levels in sperm tsRNAs, by unknown enzymes and mechanisms. b | RNA modifications may alter the secondary structure of tsRNAs, which could affect their stability and targeting specificity.