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

Key Points

  • Recent evidence increasingly supports the idea that certain ancestral life experiences acquired in the environment can be inherited by offspring; paternally acquired characteristics can be encoded in the sperm in the form of epigenetic information in addition to DNA sequences.

  • Sperm RNAs, in particular sperm microRNAs (miRNAs) and tRNA-derived small RNAs (tsRNAs), can mediate intergenerational transmission of paternally acquired phenotypes such as diet-induced metabolic disorders and mental stress phenotypes.

  • The mechanisms by which sperm RNAs respond to environmental changes and encode the acquired traits remain unclear but may involve environmental–somatic–germline interactions that may be mediated by extracellular vesicles (EVs) and mobile RNAs, and involve a breach of the somatic–germline barrier.

  • Sperm RNAs may initiate a transcriptional cascade of effects throughout embryonic development to induce a paternally acquired phenotype in offspring; how the initial effects caused by sperm RNAs are converted to a stable form of information to allow transgenerational inheritance remains a major puzzle but possibly involves interplay among transposable elements, DNA methylation and chromatin structure.

  • Emerging evidence suggests that RNA modifications in sperm RNAs have an essential role in modulating epigenetic memory. Novel methods are required to map the locations of multiple RNA modifications in each RNA species, especially for tsRNAs and miRNAs that can induce offspring phenotypes.

  • It remains unknown how many types of acquired traits can be transmitted to offspring through the germ line and under what circumstances this is likely to occur.


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.

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Figure 1: Small non-coding RNAs in mouse male germ cells.
Figure 2: Potential mechanisms involving sperm RNAs in early embryos.
Figure 3: Current knowledge of sperm RNA modifications.


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The Chen laboratory is currently supported by start-up funds from the University of Nevada, Reno School of Medicine, USA. This work is in part funded by the Ministry of Science and Technology of the People's Republic of China (2015CB943000 to Q.C. and 2016YFA0500903, 2015DFG32640 to E.D.), the National Natural Science Foundation of China (81490742, 31671568 to E.D.), the US National Institutes of Health (HD060858, HD071736 and HD085506 to W.Y.) and the John Templeton Foundation, USA (PID: 50183 to W.Y.). The authors thank all Chen laboratory members for critical discussions on the contents of the manuscript and for help in preparing the graphics and illustrations.

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Correspondence to Qi Chen, Wei Yan or Enkui Duan.

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A type of asexual reproduction that occurs when a female gamete develops a new individual without being fertilized by a male gamete

RNA-editing events

Molecular processes by which specific nucleotide sequences in an RNA molecule are changed, such as C-to-U and A-to-I editing.

Kinky-tail phenotype

A mouse phenotype characterized by a kinked tail containing a sharp bend at an angle to the main tail axis.


An epigenetic phenomenon that involves the interaction between two homologous chromosomes, resulting in either gene activation or repression at an allele.


Interaction between two alleles at a single locus during meiosis, resulting in epigenetic transfer of information from one allele to another that is heritable for generations.

Epididymal maturation

Spermatozoa from testis undergo a maturation process during transit from the proximal to the distal end of the epididymis, acquiring motility and fertility.


The mating behaviour of animals in which the females mate with more than one male in a single breeding cycle.

G-Quadruplex conformation

Guanine-rich oligonucleotides that assembled into intra- or inter-molecular guanine tetrad structures, which can be formed by both DNA and RNA.


The idea that an organism can pass on characteristics that are acquired during its lifetime to its offspring.

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Chen, Q., Yan, W. & Duan, E. Epigenetic inheritance of acquired traits through sperm RNAs and sperm RNA modifications. Nat Rev Genet 17, 733–743 (2016).

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