More than a century ago, August Weissman defined a distinction between the germline (responsible for propagating heritable information from generation to generation) and the perishable soma. A central motivation for this distinction was to argue against the inheritance of acquired characters, as the germline was partly defined by its protection from external conditions. However, recent decades have seen an explosion of studies documenting the intergenerational and transgenerational effects of environmental conditions, forcing a re-evaluation of how external signals are sensed by, or communicated to, the germline epigenome. Here, motivated by the centrality of small RNAs in paradigms of epigenetic inheritance, we review across species the myriad examples of intercellular RNA trafficking from nurse cells or somatic tissues to developing gametes.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Boskovic, A. & Rando, O. J. Transgenerational epigenetic inheritance. Annu. Rev. Genet. 52, 21–41 (2018).
Heard, E. & Martienssen, R. A. Transgenerational epigenetic inheritance: myths and mechanisms. Cell 157, 95–109 (2014).
Kawashima, T. & Berger, F. Epigenetic reprogramming in plant sexual reproduction. Nat. Rev. Genet. 15, 613–624 (2014).
Hackett, J. A. & Surani, M. A. Beyond DNA: programming and inheritance of parental methylomes. Cell 153, 737–739 (2013).
Sharma, U. Paternal contributions to offspring health: role of sperm small RNAs in intergenerational transmission of epigenetic information. Front. Cell Dev. Biol. 7, 215 (2019).
Madhani, H. D. The frustrated gene: origins of eukaryotic gene expression. Cell 155, 744–749 (2013). An excellent overview of how the need to control transposons may have driven the complexity of gene regulatory mechanisms.
Ringrose, L. & Paro, R. Epigenetic regulation of cellular memory by the Polycomb and Trithorax group proteins. Annu. Rev. Genet. 38, 413–443 (2004).
Eckersley-Maslin, M. A., Alda-Catalinas, C. & Reik, W. Dynamics of the epigenetic landscape during the maternal-to-zygotic transition. Nat. Rev. Mol. Cell Biol. 19, 436–450 (2018).
Hackett, J. A. & Surani, M. A. DNA methylation dynamics during the mammalian life cycle. Phil. Trans. R. Soc. B 368, 20110328 (2013).
Jaenisch, R. & Bird, A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat. Genet. 33, 245–254 (2003).
Jirtle, R. L. & Skinner, M. K. Environmental epigenomics and disease susceptibility. Nat. Rev. Genet. 8, 253–262 (2007).
Galan, C., Krykbaeva, M. & Rando, O. J. Early life lessons: the lasting effects of germline epigenetic information on organismal development. Mol. Metab. 38, 100924 (2020).
Rando, O. J. Daddy issues: paternal effects on phenotype. Cell 151, 702–708 (2012).
Drummond-Barbosa, D. & Spradling, A. C. Stem cells and their progeny respond to nutritional changes during Drosophila oogenesis. Dev. Biol. 231, 265–278 (2001).
McLeod, C. J., Wang, L., Wong, C. & Jones, D. L. Stem cell dynamics in response to nutrient availability. Curr. Biol. 20, 2100–2105 (2010).
LaFever, L. & Drummond-Barbosa, D. Direct control of germline stem cell division and cyst growth by neural insulin in Drosophila. Science 309, 1071–1073 (2005). Demonstrates the role of systemic factors in control of germ cell production.
Tadokoro, Y., Yomogida, K., Ohta, H., Tohda, A. & Nishimune, Y. Homeostatic regulation of germinal stem cell proliferation by the GDNF/FSH pathway. Mech. Dev. 113, 29–39 (2002).
De La Fuente, R. & Eppig, J. J. Transcriptional activity of the mouse oocyte genome: companion granulosa cells modulate transcription and chromatin remodeling. Dev. Biol. 229, 224–236 (2001).
Haig, D. Weismann Rules! OK? Epigenetics and the Lamarckian temptation. Biol. Philos. 22, 415–428 (2007).
Spradling, A. in The Development of Drosophila Melanogaster (eds Bate, M. & Arias, A. M.) 1–70 (Cold Spring Harbor Laboratory Press, 1993).
Kloc, M., Bilinski, S. & Etkin, L. D. The Balbiani body and germ cell determinants: 150 years later. Curr. Top. Dev. Biol. 59, 1–36 (2004).
Cox, R. T. & Spradling, A. C. A Balbiani body and the fusome mediate mitochondrial inheritance during Drosophila oogenesis. Development 130, 1579–1590 (2003).
Tworzydlo, W., Sekula, M. & Bilinski, S. M. Transmission of functional, wild-type mitochondria and the fittest mtDNA to the next generation: bottleneck phenomenon, Balbiani body, and mitophagy. Genes 11, 104 (2020).
Orr-Weaver, T. L. When bigger is better: the role of polyploidy in organogenesis. Trends Genet. 31, 307–315 (2015).
Strome, S. & Lehmann, R. Germ versus soma decisions: lessons from flies and worms. Science 316, 392–393 (2007).
Malone, C. D. et al. Specialized piRNA pathways act in germline and somatic tissues of the Drosophila ovary. Cell 137, 522–535 (2009).
Tiwari, B. et al. Retrotransposons mimic germ plasm determinants to promote transgenerational inheritance. Curr. Biol. 27, 3010–3016.e3 (2017).
Wang, L., Dou, K., Moon, S., Tan, F. J. & Zhang, Z. Z. Hijacking oogenesis enables massive propagation of LINE and retroviral transposons. Cell 174, 1082–1094.e12 (2018).
Brennecke, J. et al. Discrete small RNA-generating loci as master regulators of transposon activity in Drosophila. Cell 128, 1089–1103 (2007).
Gunawardane, L. S. et al. A slicer-mediated mechanism for repeat-associated siRNA 5′ end formation in Drosophila. Science 315, 1587–1590 (2007).
Vagin, V. V. et al. A distinct small RNA pathway silences selfish genetic elements in the germline. Science 313, 320–324 (2006).
Klattenhoff, C. & Theurkauf, W. Biogenesis and germline functions of piRNAs. Development 135, 3–9 (2008).
Pepling, M. E., Wilhelm, J. E., O’Hara, A. L., Gephardt, G. W. & Spradling, A. C. Mouse oocytes within germ cell cysts and primordial follicles contain a Balbiani body. Proc. Natl Acad. Sci. USA 104, 187–192 (2007). Discovery of Balbiani bodies in mouse oocytes.
Lei, L. & Spradling, A. C. Mouse oocytes differentiate through organelle enrichment from sister cyst germ cells. Science 352, 95–99 (2016).
Wolke, U., Jezuit, E. A. & Priess, J. R. Actin-dependent cytoplasmic streaming in C. elegans oogenesis. Development 134, 2227–2236 (2007).
Raiders, S. A., Eastwood, M. D., Bacher, M. & Priess, J. R. Binucleate germ cells in Caenorhabditis elegans are removed by physiological apoptosis. PLoS Genet. 14, e1007417 (2018).
Braun, R. E., Behringer, R. R., Peschon, J. J., Brinster, R. L. & Palmiter, R. D. Genetically haploid spermatids are phenotypically diploid. Nature 337, 373–376 (1989). Demonstration of cytoplasmic RNA sharing between haploid sperm in mice.
Ventela, S., Toppari, J. & Parvinen, M. Intercellular organelle traffic through cytoplasmic bridges in early spermatids of the rat: mechanisms of haploid gene product sharing. Mol. Biol. Cell 14, 2768–2780 (2003).
Veron, N. et al. Retention of gene products in syncytial spermatids promotes non-Mendelian inheritance as revealed by the T complex responder. Genes Dev. 23, 2705–2710 (2009).
Bhutani, K. et al. Widespread haploid-biased gene expression enables sperm-level natural selection. Science 371, eabb1723 (2021). Mammalian sperm retain a subset of haploid-expressed mRNAs.
Dodson, A. E. & Kennedy, S. Phase separation in germ cells and development. Dev. Cell 55, 4–17 (2020).
Allan, D. J., Harmon, B. V. & Roberts, S. A. Spermatogonial apoptosis has three morphologically recognizable phases and shows no circadian rhythm during normal spermatogenesis in the rat. Cell Prolif. 25, 241–250 (1992).
Shaha, C., Tripathi, R. & Mishra, D. P. Male germ cell apoptosis: regulation and biology. Phil. Trans. R. Soc. B 365, 1501–1515 (2010).
McCue, A. D., Cresti, M., Feijo, J. A. & Slotkin, R. K. Cytoplasmic connection of sperm cells to the pollen vegetative cell nucleus: potential roles of the male germ unit revisited. J. Exp. Bot. 62, 1621–1631 (2011).
Slotkin, R. K. et al. Epigenetic reprogramming and small RNA silencing of transposable elements in pollen. Cell 136, 461–472 (2009).
Martinez, G., Panda, K., Kohler, C. & Slotkin, R. K. Silencing in sperm cells is directed by RNA movement from the surrounding nurse cell. Nat. Plants 2, 16030 (2016). Demonstration of siRNA trafficking from vegetative cells to sperm cells in Arabidopsis.
Grant-Downton, R. et al. Artificial microRNAs reveal cell-specific differences in small RNA activity in pollen. Curr. Biol. 23, R599–R601 (2013).
Ibarra, C. A. et al. Active DNA demethylation in plant companion cells reinforces transposon methylation in gametes. Science 337, 1360–1364 (2012).
Erdmann, R. M. et al. Molecular movement in the Arabidopsis thaliana female gametophyte. Plant. Reprod. 30, 141–146 (2017).
Prescott, D. M. The DNA of ciliated protozoa. Microbiol. Rev. 58, 233–267 (1994).
Tucker, J. B., Beisson, J., Roche, D. L. & Cohen, J. Microtubules and control of macronuclear ‘amitosis’ in Paramecium. J. Cell Sci. 44, 135–151 (1980).
Bracht, J. R. et al. Genomes on the edge: programmed genome instability in ciliates. Cell 152, 406–416 (2013).
Parfrey, L. W., Lahr, D. J., Knoll, A. H. & Katz, L. A. Estimating the timing of early eukaryotic diversification with multigene molecular clocks. Proc. Natl Acad. Sci. USA 108, 13624–13629 (2011).
Chalker, D. L. & Yao, M. C. Nongenic, bidirectional transcription precedes and may promote developmental DNA deletion in Tetrahymena thermophila. Genes Dev. 15, 1287–1298 (2001).
Lepere, G., Betermier, M., Meyer, E. & Duharcourt, S. Maternal noncoding transcripts antagonize the targeting of DNA elimination by scanRNAs in Paramecium tetraurelia. Genes Dev. 22, 1501–1512 (2008).
Fang, W., Wang, X., Bracht, J. R., Nowacki, M. & Landweber, L. F. Piwi-interacting RNAs protect DNA against loss during Oxytricha genome rearrangement. Cell 151, 1243–1255 (2012).
Orgebin-Crist, M. C. Sperm maturation in rabbit epididymis. Nature 216, 816–818 (1967). Epididymal transit is required for the acquisition of sperm motility and fertility in mammals.
Bedford, J. M. Effects of duct ligation on the fertilizing ability of spermatozoa from different regions of the rabbit epididymis. J. Exp. Zool. 166, 271–281 (1967).
Gervasi, M. G. & Visconti, P. E. Molecular changes and signaling events occurring in spermatozoa during epididymal maturation. Andrology 5, 204–218 (2017).
Domeniconi, R. F., Souza, A. C., Xu, B., Washington, A. M. & Hinton, B. T. Is the epididymis a series of organs placed side by side? Biol. Reprod. 95, 10 (2016).
Johnston, D. S. et al. The mouse epididymal transcriptome: transcriptional profiling of segmental gene expression in the epididymis. Biol. Reprod. 73, 404–413 (2005).
Frenette, G. & Sullivan, R. Prostasome-like particles are involved in the transfer of P25b from the bovine epididymal fluid to the sperm surface. Mol. Reprod. Dev. 59, 115–121 (2001).
Sullivan, R., Frenette, G. & Girouard, J. Epididymosomes are involved in the acquisition of new sperm proteins during epididymal transit. Asian J. Androl. 9, 483–491 (2007). Vesicles released by the eididymis fuse with sperm to deliver proteins important for fertility in mammals.
Sullivan, R. & Saez, F. Epididymosomes, prostasomes, and liposomes: their roles in mammalian male reproductive physiology. Reproduction 146, R21–R35 (2013).
Krapf, D. et al. cSrc is necessary for epididymal development and is incorporated into sperm during epididymal transit. Dev. Biol. 369, 43–53 (2012).
Tamessar, C. T. et al. Roles of male reproductive tract extracellular vesicles in reproduction. Am. J. Reprod. Immunol. 85, e13338 (2021).
Peng, H. et al. A novel class of tRNA-derived small RNAs extremely enriched in mature mouse sperm. Cell Res. 22, 1609–1612 (2012).
Nixon, B. et al. The microRNA signature of mouse spermatozoa is substantially modified during epididymal maturation. Biol. Reprod. 93, 91 (2015).
Sharma, U. et al. Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals. Science 351, 391–396 (2016). Survery of small RNA dynamics during post-testicular maturation of mammalian sperm.
Sellem, E. et al. Dynamics of cattle sperm sncRNAs during maturation, from testis to ejaculated sperm. Epigenetics Chromatin 14, 24 (2021).
Johnson, G. D. et al. Cleavage of rRNA ensures translational cessation in sperm at fertilization. Mol. Hum. Reprod. 17, 721–726 (2011).
Gou, L. T. et al. Pachytene piRNAs instruct massive mRNA elimination during late spermiogenesis. Cell Res. 24, 680–700 (2014).
Goh, W. S. et al. piRNA-directed cleavage of meiotic transcripts regulates spermatogenesis. Genes Dev. 29, 1032–1044 (2015).
Zhang, P. et al. MIWI and piRNA-mediated cleavage of messenger RNAs in mouse testes. Cell Res. 25, 193–207 (2015).
Reilly, J. N. et al. Characterisation of mouse epididymosomes reveals a complex profile of microRNAs and a potential mechanism for modification of the sperm epigenome. Sci. Rep. 6, 31794 (2016).
Sharma, U. et al. Small RNAs are trafficked from the epididymis to developing mammalian sperm. Dev. Cell 46, 481–494.e6 (2018).
Belleannee, C., Calvo, E., Caballero, J. & Sullivan, R. Epididymosomes convey different repertoires of microRNAs throughout the bovine epididymis. Biol. Reprod. 89, 30 (2013).
Twenter, H. et al. Transfer of microRNAs from epididymal epithelium to equine spermatozoa. J. Equine Vet. Sci. 87, 102841 (2020).
Rompala, G. R., Ferguson, C. & Homanics, G. E. Coincubation of sperm with epididymal extracellular vesicle preparations from chronic intermittent ethanol-treated mice is sufficient to impart anxiety-like and ethanol-induced behaviors to adult progeny. Alcohol 87, 111–120 (2020). Functional role for epididymosomal RNA delivery to sperm in control of offspring phenotype in mice is shown.
Chan, J. C. et al. Reproductive tract extracellular vesicles are sufficient to transmit intergenerational stress and program neurodevelopment. Nat. Commun. 11, 1499 (2020).
Capra, E. & Lange-Consiglio, A. The biological function of extracellular vesicles during fertilization, early embryo-maternal crosstalk and their involvement in reproduction: review and overview. Biomolecules 10, 1510 (2020).
Pons-Rejraji, H. et al. Prostasomes: inhibitors of capacitation and modulators of cellular signalling in human sperm. Int. J. Androl. 34, 568–580 (2011).
Chen, X. et al. Early cleavage of preimplantation embryos is regulated by tRNA(Gln-TTG)-derived small RNAs present in mature spermatozoa. J. Biol. Chem. 295, 10885–10900 (2020).
Fabiani, R., Johansson, L., Lundkvist, O. & Ronquist, G. Enhanced recruitment of motile spermatozoa by prostasome inclusion in swim-up medium. Hum. Reprod. 9, 1485–1489 (1994).
Park, K. H. et al. Ca2+ signaling tools acquired from prostasomes are required for progesterone-induced sperm motility. Sci. Signal. 4, ra31 (2011).
Corrigan, L. et al. BMP-regulated exosomes from Drosophila male reproductive glands reprogram female behavior. J. Cell Biol. 206, 671–688 (2014).
Hopkins, B. R. et al. BMP signaling inhibition in Drosophila secondary cells remodels the seminal proteome and self and rival ejaculate functions. Proc. Natl Acad. Sci. USA 116, 24719–24728 (2019).
Buccione, R., Schroeder, A. C. & Eppig, J. J. Interactions between somatic cells and germ cells throughout mammalian oogenesis. Biol. Reprod. 43, 543–547 (1990).
Su, Y. Q., Sugiura, K. & Eppig, J. J. Mouse oocyte control of granulosa cell development and function: paracrine regulation of cumulus cell metabolism. Semin. Reprod. Med. 27, 32–42 (2009).
Albertini, D. F., Combelles, C. M., Benecchi, E. & Carabatsos, M. J. Cellular basis for paracrine regulation of ovarian follicle development. Reproduction 121, 647–653 (2001).
Clarke, H. J. Regulation of germ cell development by intercellular signaling in the mammalian ovarian follicle. Wiley Interdiscip. Rev. Dev. Biol. 7, e294 (2018).
Coticchio, G. et al. Oocyte maturation: gamete-somatic cells interactions, meiotic resumption, cytoskeletal dynamics and cytoplasmic reorganization. Hum. Reprod. update 21, 427–454 (2015).
Macaulay, A. D. et al. The gametic synapse: RNA transfer to the bovine oocyte. Biol. Reprod. 91, 90 (2014).
Macaulay, A. D. et al. Cumulus cell transcripts transit to the bovine oocyte in preparation for maturation. Biol. Reprod. 94, 16 (2016). Shows RNA trafficking from granulosa cells to mammalian oocytes.
Whitten, S. J. & Miller, M. A. The role of gap junctions in Caenorhabditis elegans oocyte maturation and fertilization. Dev. Biol. 301, 432–446 (2007).
Li, C. et al. Collapse of germline piRNAs in the absence of Argonaute3 reveals somatic piRNAs in flies. Cell 137, 509–521 (2009).
Pelisson, A. et al. Gypsy transposition correlates with the production of a retroviral envelope-like protein under the tissue-specific control of the Drosophila flamenco gene. EMBO J. 13, 4401–4411 (1994).
Song, S. U., Kurkulos, M., Boeke, J. D. & Corces, V. G. Infection of the germ line by retroviral particles produced in the follicle cells: a possible mechanism for the mobilization of the gypsy retroelement of Drosophila. Development 124, 2789–2798 (1997).
Machtinger, R., Laurent, L. C. & Baccarelli, A. A. Extracellular vesicles: roles in gamete maturation, fertilization and embryo implantation. Hum. Reprod. Update 22, 182–193 (2016).
Fire, A. et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806–811 (1998). Describes the discovery of RNAi.
Grishok, A., Tabara, H. & Mello, C. C. Genetic requirements for inheritance of RNAi in C. elegans. Science 287, 2494–2497 (2000).
Alcazar, R. M., Lin, R. & Fire, A. Z. Transmission dynamics of heritable silencing induced by double-stranded RNA in Caenorhabditis elegans. Genetics 180, 1275–1288 (2008).
Timmons, L. & Fire, A. Specific interference by ingested dsRNA. Nature 395, 854 (1998).
Winston, W. M., Molodowitch, C. & Hunter, C. P. Systemic RNAi in C. elegans requires the putative transmembrane protein SID-1. Science 295, 2456–2459 (2002). Genetic identification of factors required for systemic RNA trafficking in worms.
Marre, J., Traver, E. C. & Jose, A. M. Extracellular RNA is transported from one generation to the next in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 113, 12496–12501 (2016).
Devanapally, S., Ravikumar, S. & Jose, A. M. Double-stranded RNA made in C. elegans neurons can enter the germline and cause transgenerational gene silencing. Proc. Natl Acad. Sci. USA 112, 2133–2138 (2015). Demonstration of functional RNA trafficking from neurons to germ line in worms.
Posner, R. et al. Neuronal small RNAs control behavior transgenerationally. Cell 177, 1814–1826.e15 (2019).
Tijsterman, M., May, R. C., Simmer, F., Okihara, K. L. & Plasterk, R. H. Genes required for systemic RNA interference in Caenorhabditis elegans. Curr. Biol. 14, 111–116 (2004).
Moore, R. S., Kaletsky, R. & Murphy, C. T. Piwi/PRG-1 argonaute and TGF-beta mediate transgenerational learned pathogenic avoidance. Cell 177, 1827–1841.e12 (2019). C. elegans behaviours are transmitted transgenerationally via small RNAs.
Kaletsky, R. et al. C. elegans interprets bacterial non-coding RNAs to learn pathogenic avoidance. Nature 586, 445–451 (2020).
Voinnet, O. & Baulcombe, D. C. Systemic signalling in gene silencing. Nature 389, 553 (1997).
Palauqui, J. C., Elmayan, T., Pollien, J. M. & Vaucheret, H. Systemic acquired silencing: transgene-specific post-transcriptional silencing is transmitted by grafting from silenced stocks to non-silenced scions. EMBO J. 16, 4738–4745 (1997).
Voinnet, O., Vain, P., Angell, S. & Baulcombe, D. C. Systemic spread of sequence-specific transgene RNA degradation in plants is initiated by localized introduction of ectopic promoterless DNA. Cell 95, 177–187 (1998). Describes systemic RNA trafficking in plants.
Pant, B. D., Buhtz, A., Kehr, J. & Scheible, W. R. MicroRNA399 is a long-distance signal for the regulation of plant phosphate homeostasis. Plant J. 53, 731–738 (2008).
Chitwood, D. H. et al. Pattern formation via small RNA mobility. Genes Dev. 23, 549–554 (2009).
Melnyk, C. W., Molnar, A. & Baulcombe, D. C. Intercellular and systemic movement of RNA silencing signals. EMBO J. 30, 3553–3563 (2011).
Melnyk, C. W., Molnar, A., Bassett, A. & Baulcombe, D. C. Mobile 24 nt small RNAs direct transcriptional gene silencing in the root meristems of Arabidopsis thaliana. Curr. Biol. B 21, 1678–1683 (2011).
Molnar, A. et al. Small silencing RNAs in plants are mobile and direct epigenetic modification in recipient cells. Science 328, 872–875 (2010).
Tamiru, M., Hardcastle, T. J. & Lewsey, M. G. Regulation of genome-wide DNA methylation by mobile small RNAs. N. Phytol. 217, 540–546 (2018).
Thieme, C. J. et al. Endogenous Arabidopsis messenger RNAs transported to distant tissues. Nat. Plants 1, 15025 (2015).
Zhang, W. et al. tRNA-related sequences trigger systemic mRNA transport in plants. Plant Cell 28, 1237–1249 (2016).
Brosnan, C. A. & Voinnet, O. Cell-to-cell and long-distance siRNA movement in plants: mechanisms and biological implications. Curr. Opin. Plant Biol. 14, 580–587 (2011).
Sarkies, P. & Miska, E. A. Small RNAs break out: the molecular cell biology of mobile small RNAs. Nat. Rev. Mol. Cell Biol. 15, 525–535 (2014).
Devers, E. A. et al. Movement and differential consumption of short interfering RNA duplexes underlie mobile RNA interference. Nat. Plants 6, 789–799 (2020).
Schmidt, A., Schmid, M. W. & Grossniklaus, U. Plant germline formation: common concepts and developmental flexibility in sexual and asexual reproduction. Development 142, 229–241 (2015).
Zhang, W. et al. Graft-transmissible movement of inverted-repeat-induced siRNA signals into flowers. Plant J. 80, 106–121 (2014).
Kasai, A., Bai, S., Hojo, H. & Harada, T. Epigenome editing of potato by grafting using transgenic tobacco as siRNA donor. PLoS ONE 11, e0161729 (2016).
Virdi, K. S. et al. Arabidopsis MSH1 mutation alters the epigenome and produces heritable changes in plant growth. Nat. Commun. 6, 6386 (2015).
Kundariya, H. et al. MSH1-induced heritable enhanced growth vigor through grafting is associated with the RdDM pathway in plants. Nat. Commun. 11, 5343 (2020).
Cossetti, C. et al. Soma-to-germline transmission of RNA in mice xenografted with human tumour cells: possible transport by exosomes. PLoS ONE 9, e101629 (2014).
O’Brien, E. A., Ensbey, K. S., Day, B. W., Baldock, P. A. & Barry, G. Direct evidence for transport of RNA from the mouse brain to the germline and offspring. BMC Biol. 18, 45 (2020).
Zhang, Y. et al. Dnmt2 mediates intergenerational transmission of paternally acquired metabolic disorders through sperm small non-coding RNAs. Nat. Cell Biol. 20, 535–540 (2018).
Rompala, G. R. et al. Heavy chronic intermittent ethanol exposure alters small noncoding RNAs in mouse sperm and epididymosomes. Front. Genet. 9, 32 (2018).
Yoshida, K. et al. ATF7-dependent epigenetic changes are required for the intergenerational effect of a paternal low-protein diet. Mol. Cell 78, 445–458.e6 (2020).
Nilsson, E. E., Maamar, M. B. & Skinner, M. K. Environmentally induced epigenetic transgenerational inheritance and the weismann barrier: the dawn of neo-Lamarckian theory. J. Dev. Biol. 8, 28 (2020).
Janke, R., Dodson, A. E. & Rine, J. Metabolism and epigenetics. Annu. Rev. Cell Dev. Biol. 31, 473–496 (2015).
Sharma, U. & Rando, O. J. Metabolic inputs into the epigenome. Cell Metab. 25, 544–558 (2017).
Padmanabhan, N. et al. Mutation in folate metabolism causes epigenetic instability and transgenerational effects on development. Cell 155, 81–93 (2013).
Lismer, A. et al. Histone H3 lysine 4 trimethylation in sperm is transmitted to the embryo and associated with diet-induced phenotypes in the offspring. Dev. Cell 56, 671–686.e6 (2021).
Watkins, A. J. et al. Paternal diet programs offspring health through sperm- and seminal plasma-specific pathways in mice. Proc. Natl Acad. Sci. USA 115, 10064–10069 (2018).
Kimble, J. Alterations in cell lineage following laser ablation of cells in the somatic gonad of Caenorhabditis elegans. Dev. Biol. 87, 286–300 (1981).
Kimble, J. E. & White, J. G. On the control of germ cell development in Caenorhabditis elegans. Dev. Biol. 81, 208–219 (1981).
Hai, Y. et al. The roles and regulation of Sertoli cells in fate determinations of spermatogonial stem cells and spermatogenesis. Semin. Cell Dev. Biol. 29, 66–75 (2014).
Arteaga-Vazquez, M. A. & Chandler, V. L. Paramutation in maize: RNA mediated trans-generational gene silencing. Curr. Opin. Genet. Dev. 20, 156–163 (2010). Excellent review of paramutation, the first epigenetic inheritance paradigm characterized in detail.
Chen, Q. et al. Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder. Science 351, 397–400 (2016).
Gapp, K. et al. Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice. Nat. Neurosci. 17, 667–669 (2014).
Sarker, G. et al. Maternal overnutrition programs hedonic and metabolic phenotypes across generations through sperm tsRNAs. Proc. Natl Acad. Sci. USA 116, 10547–10556 (2019).
Wagner, K. D. et al. RNA induction and inheritance of epigenetic cardiac hypertrophy in the mouse. Dev. Cell 14, 962–969 (2008).
Grandjean, V. et al. RNA-mediated paternal heredity of diet-induced obesity and metabolic disorders. Sci. Rep. 5, 18193 (2015).
Rodgers, A. B., Morgan, C. P., Leu, N. A. & Bale, T. L. Transgenerational epigenetic programming via sperm microRNA recapitulates effects of paternal stress. Proc. Natl Acad. Sci. USA 112, 13699–13704 (2015).
The authors thank V. Rinaldi and C. Galan for critical reading of the manuscript, and K. Slotkin and J. McCarrey for helpful discussions. This work was supported by Templeton Foundation Grant 61350 to O.J.R. and a Pew Biomedical Scholars Award to C.C.C.
The authors declare no competing interests.
Peer review information
Nature Reviews Genetics thanks the reviewer(s) for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- Selfish genetic elements
DNA sequences that can move within a genome and generate multiple copies, often to the detriment of the host, most famously, transposons.
- Balbiani body
A subcellular structure in oocytes comprising mitochondria, endoplasmic reticulum and Golgi membranes, and germ plasm RNAs and proteins.
To copy parts of the genome without mitosis, leading either to whole genome polyploidy or to selective amplification of specific genomic loci.
Effector proteins that bind to small RNAs such as short interfering RNAs, microRNAs and PIWI-interacting RNAs, and use these small RNAs to target homologous RNAs such as transposon RNAs.
A structure, often formed by cell fusion or nuclear division without cell division, in which multiple nuclei share the same cytoplasm.
The oocyte membrane.
- RNA-directed DNA methylation (RdDM) pathway
A pathway in plants in which small RNAs direct cytosine methylation at genomic target sites.
About this article
Cite this article
Conine, C.C., Rando, O.J. Soma-to-germline RNA communication. Nat Rev Genet (2021). https://doi.org/10.1038/s41576-021-00412-1