Molecular Genetics and Genomics

, Volume 294, Issue 1, pp 1–11 | Cite as

The influence of paternal diet on sncRNA-mediated epigenetic inheritance

  • Line Katrine Klastrup
  • Stine Thorhauge Bak
  • Anders Lade NielsenEmail author


The risk of developing metabolic diseases is conferred by genetic predisposition from risk genes and by environmental exposures that can manifest in epigenetic changes. The global rise in obesity and type II diabetes has motivated a search for the epigenetic factors underlying these diseases. The possibility of transgenerational inheritance of epigenetic changes raises questions regarding how spermatozoa transmit acquired epigenetic changes that affect the metabolic health of the next generation. The purpose of this review is to describe current key literature concerning small non-coding RNA (sncRNA), specifically (1) the effects of high-fat or low-protein diets on sncRNA presence in spermatozoa; (2) sncRNA transmission from father to offspring; and (3) the functional effects of inherited sncRNA on offspring metabolic phenotype. Current research has identified alterations in the content of sncRNA subtypes, including microRNA (miRNA), Piwi-interacting RNA (piRNA), and transferRNA (tRNA)-derived small non-coding RNA (tsncRNA), in spermatozoa in response to both high-fat diets and low-protein diets. The altered content of spermatozoa sncRNA due to high-fat diets was associated with a changed phenotype in offspring, with offspring displaying insulin resistance, altered body weight, and glucose intolerance. The altered sncRNA content of spermatozoa due to a low-protein diet was associated with altered levels of lipid metabolites in offspring and decreased expression of specific genes starting in two-cell embryos. The current literature suggests that sncRNAs mediate paternal intergenerational epigenetic inheritance and thus has a direct functional importance, as well as possess biomarker potential, for metabolic diseases. Further research is urgently required to identify the specific sncRNAs with the most profound impacts.


Epigenetics Phenotype inheritance Small non-coding RNA Epitranscriptome Epigenome 



Endogenous small interfering RNA


High-fat diet


Low-protein diet


Messenger RNA




Piwi-interacting RNA


Ribosomal RNA


rRNA-derived small RNA


Small cytoplasmic RNA


SnoRNA-derived small RNA


Small nuclear RNA


Small non-coding RNAs


Small nucleolar RNA


Transfer RNA


tRNA halves


tRNA-derived small non-coding RNA


tRNA-derived fragments


Pre-tRNA-derived small RNA



Stine Thorhauge Bak was supported by a Ph.D. fellowship from Health, Aarhus University, Denmark.

Author contributions

Study conception and design was performed by Line Katrine Klastrup (LKK) and Anders Lade Nielsen (ALN). Study analysis and interpretation of data were performed by LKK, Stine Thorhauge Bak (STB) and ALN. Drafting of the manuscript was performed by LKK, STB and ALN. All authors approved the final version of the manuscript. ALN is guarantor for the article and accepts full responsibility for the work, the conduct of the study, and controlled the decision to publish.



Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.


  1. Aiken CE, Ozanne SE (2014) Transgenerational developmental programming. Hum Reprod Update 20:63–75CrossRefGoogle Scholar
  2. Ajslev TA, Angquist L, Silventoinen K, Baker JL, Sorensen TI (2015) Stable intergenerational associations of childhood overweight during the development of the obesity epidemic. Obesity (Silver Spring) 23:1279–1287CrossRefGoogle Scholar
  3. Campos EI, Stafford JM, Reinberg D (2014) Epigenetic inheritance: histone bookmarks across generations. Trends Cell Biol 24:664–674CrossRefGoogle Scholar
  4. Carone BR, Fauquier L, Habib N, Shea JM, Hart CE, Li R, Bock C, Li C, Gu H, Zamore PD, Meissner A, Weng Z, Hofmann HA, Friedman N, Rando OJ (2010) Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell 143:1084–1096CrossRefGoogle Scholar
  5. Carthew RW, Sontheimer EJ (2009) Origins and mechanisms of miRNAs and siRNAs. Cell 136:642–655CrossRefGoogle Scholar
  6. Cech TR, Steitz JA (2014) The noncoding RNA revolution-trashing old rules to forge new ones. Cell 157:77–94CrossRefGoogle Scholar
  7. Chatzigeorgiou A, Halapas A, Kalafatakis K, Kamper E (2009) The use of animal models in the study of diabetes mellitus. In Vivo 23:245–258Google Scholar
  8. Chen Q, Yan M, Cao Z, Li X, Zhang Y, Shi J, Feng GH, Peng H, Zhang X, Zhang Y, Qian J, Duan E, Zhai Q, Zhou Q (2016a) Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder. Science 351:397–400CrossRefGoogle Scholar
  9. Chen Q, Yan W, Duan E (2016b) Epigenetic inheritance of acquired traits through sperm RNAs and sperm RNA modifications. Nat Rev Genet 17:733–743CrossRefGoogle Scholar
  10. Conine CC, Sun F, Song L, Rivera-Perez JA, Rando OJ (2018) Small RNAs gained during epididymal transit of sperm are essential for embryonic development in mice. Dev Cell 46(4):470–480. CrossRefGoogle Scholar
  11. Cropley JE, Eaton SA, Aiken A, Young PE, Giannoulatou E, Ho JW, Buckland ME, Keam SP, Hutvagner G, Humphreys DT, Langley KG, Henstridge DC, Martin DI, Febbraio MA, Suter CM (2016) Male-lineage transmission of an acquired metabolic phenotype induced by grand-paternal obesity. Mol Metab 5:699–708CrossRefGoogle Scholar
  12. Daraki V, Georgiou V, Papavasiliou S, Chalkiadaki G, Karahaliou M, Koinaki S, Sarri K, Vassilaki M, Kogevinas M, Chatzi L (2015) Metabolic profile in early pregnancy is associated with offspring adiposity at 4 years of age: the Rhea pregnancy cohort Crete, Greece. PLoS One 10:e0126327CrossRefGoogle Scholar
  13. Daxinger L, Whitelaw E (2012) Understanding transgenerational epigenetic inheritance via the gametes in mammals. Nat Rev Genet 13:153–162CrossRefGoogle Scholar
  14. de Castro Barbosa T, Ingerslev LR, Alm PS, Versteyhe S, Massart J, Rasmussen M, Donkin I, Sjogren R, Mudry JM, Vetterli L, Gupta S, Krook A, Zierath JR, Barres R (2016) High-fat diet reprograms the epigenome of rat spermatozoa and transgenerationally affects metabolism of the offspring. Mol Metab 5:184–197CrossRefGoogle Scholar
  15. Donkin I, Versteyhe S, Ingerslev LR, Qian K, Mechta M, Nordkap L, Mortensen B, Appel EV, Jorgensen N, Kristiansen VB, Hansen T, Workman CT, Zierath JR, Barres R (2016) Obesity and bariatric surgery drive epigenetic variation of spermatozoa in humans. Cell Metab 23:369–378CrossRefGoogle Scholar
  16. Eaton SA, Jayasooriah N, Buckland ME, Martin DI, Cropley JE, Suter CM (2015) Roll over Weismann: extracellular vesicles in the transgenerational transmission of environmental effects. Epigenomics 7:1165–1171CrossRefGoogle Scholar
  17. Fullston T, Ohlsson Teague EM, Palmer NO, DeBlasio MJ, Mitchell M, Corbett M, Print CG, Owens JA, Lane M (2013) Paternal obesity initiates metabolic disturbances in two generations of mice with incomplete penetrance to the F2 generation and alters the transcriptional profile of testis and sperm microRNA content. FASEB J 27:4226–4243CrossRefGoogle Scholar
  18. Fullston T, Ohlsson-Teague EM, Print CG, Sandeman LY, Lane M (2016) Sperm microRNA content is altered in a mouse model of male obesity, but the same suite of microRNAs are not altered in offspring’s sperm. PLoS One 11:e0166076CrossRefGoogle Scholar
  19. Gapp K, Jawaid A, Sarkies P, Bohacek J, Pelczar P, Prados J, Farinelli L, Miska E, Mansuy IM (2014) Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice. Nat Neurosci 17:667–669CrossRefGoogle Scholar
  20. Garcia-Lopez J, Alonso L, Cardenas DB, Artaza-Alvarez H, Hourcade Jde D, Martinez S, Brieno-Enriquez MA, Del Mazo J (2015) Diversity and functional convergence of small noncoding RNAs in male germ cell differentiation and fertilization. RNA 21:946–962CrossRefGoogle Scholar
  21. Gold HB, Jung YH, Corces VG (2018) Not just heads and tails: the complexity of the sperm epigenome. J Biol Chem 293(36):13815–13820CrossRefGoogle Scholar
  22. Grandjean V, Fourre S, De Abreu DA, Derieppe MA, Remy JJ, Rassoulzadegan M (2015) RNA-mediated paternal heredity of diet-induced obesity and metabolic disorders. Sci Rep 5:18193CrossRefGoogle Scholar
  23. Heard E, Martienssen RA (2014) Transgenerational epigenetic inheritance: myths and mechanisms. Cell 157:95–109CrossRefGoogle Scholar
  24. Hoernes TP, Erlacher MD (2017) Translating the epitranscriptome. Wiley Interdiscip Rev RNA. Google Scholar
  25. Hombach S, Kretz M (2016) Non-coding RNAs: classification, biology and functioning. Adv Exp Med Biol 937:3–17CrossRefGoogle Scholar
  26. Hosken DJ, Hodgson DJ (2014) Why do sperm carry RNA? Relatedness, conflict, and control. Trends Ecol Evol 29:451–455CrossRefGoogle Scholar
  27. Huypens P, Sass S, Wu M, Dyckhoff D, Tschop M, Theis F, Marschall S, Hrabe de Angelis M, Beckers J (2016) Epigenetic germline inheritance of diet-induced obesity and insulin resistance. Nat Genet 48:497–499CrossRefGoogle Scholar
  28. Illum LRH, Bak ST, Lund S, Nielsen AL (2018) DNA methylation in epigenetic inheritance of metabolic diseases through the male germ line. J Mol Endocrinol 60:R39–R56CrossRefGoogle Scholar
  29. Iwasaki YW, Siomi MC, Siomi H (2015) PIWI-Interacting RNA: its biogenesis and functions. Annu Rev Biochem 84:405–433CrossRefGoogle Scholar
  30. Kiani J, Grandjean V, Liebers R, Tuorto F, Ghanbarian H, Lyko F, Cuzin F, Rassoulzadegan M (2013) RNA-mediated epigenetic heredity requires the cytosine methyltransferase Dnmt2. PLoS Genet 9:e1003498CrossRefGoogle Scholar
  31. Kumar P, Kuscu C, Dutta A (2016) Biogenesis and function of transfer RNA-related fragments (tRFs). Trends Biochem Sci 41:679–689CrossRefGoogle Scholar
  32. Kummitha CM, Kalhan SC, Saidel GM, Lai N (2014) Relating tissue/organ energy expenditure to metabolic fluxes in mouse and human: experimental data integrated with mathematical modeling. Physiol Rep 2(9):e12159. CrossRefGoogle Scholar
  33. Lin S, Lin Y, Nery JR, Urich MA, Breschi A, Davis CA, Dobin A, Zaleski C, Beer MA, Chapman WC, Gingeras TR, Ecker JR, Snyder MP (2014) Comparison of the transcriptional landscapes between human and mouse tissues. Proc Natl Acad Sci USA 111:17224–17229CrossRefGoogle Scholar
  34. Marczylo EL, Amoako AA, Konje JC, Gant TW, Marczylo TH (2012) Smoking induces differential miRNA expression in human spermatozoa: a potential transgenerational epigenetic concern? Epigenetics 7:432–439CrossRefGoogle Scholar
  35. Miller D, Brinkworth M, Iles D (2010) Paternal DNA packaging in spermatozoa: more than the sum of its parts? DNA, histones, protamines and epigenetics. Reproduction 139:287–301CrossRefGoogle Scholar
  36. Nilsson EE, Sadler-Riggleman I, Skinner MK (2018) Environmentally induced epigenetic transgenerational inheritance of disease. Environ Epigenet 4:dvy016CrossRefGoogle Scholar
  37. Pembrey M, Saffery R, Bygren LO, Network in Epigenetic Epidemiology, Network in Epigenetic Epidemiology (2014) Human transgenerational responses to early-life experience: potential impact on development, health and biomedical research. J Med Genet 51:563–572CrossRefGoogle Scholar
  38. Peng H, Shi J, Zhang Y, Zhang H, Liao S, Li W, Lei L, Han C, Ning L, Cao Y, Zhou Q, Chen Q, Duan E (2012) A novel class of tRNA-derived small RNAs extremely enriched in mature mouse sperm. Cell Res 22:1609–1612CrossRefGoogle Scholar
  39. Radford EJ, Ito M, Shi H, Corish JA, Yamazawa K, Isganaitis E, Seisenberger S, Hore TA, Reik W, Erkek S, Peters A, Patti ME, Ferguson-Smith AC (2014) In utero effects. In utero undernourishment perturbs the adult sperm methylome and intergenerational metabolism. Science 345:1255903CrossRefGoogle Scholar
  40. Rando OJ (2016) Intergenerational transfer of epigenetic information in sperm. Cold Spring Harb Perspect Med 6(5):a22988. CrossRefGoogle Scholar
  41. Rando OJ, Simmons RA (2015) I’m eating for two: parental dietary effects on offspring metabolism. Cell 161:93–105CrossRefGoogle Scholar
  42. Rechavi O, Houri-Ze’evi L, Anava S, Goh WSS, Kerk SY, Hannon GJ, Hobert O (2014) Starvation-induced transgenerational inheritance of small RNAs in C. elegans. Cell 158:277–287CrossRefGoogle Scholar
  43. Reilly JN, McLaughlin EA, Stanger SJ, Anderson AL, Hutcheon K, Church K, Mihalas BP, Tyagi S, Holt JE, Eamens AL, Nixon B (2016) Characterisation of mouse epididymosomes reveals a complex profile of microRNAs and a potential mechanism for modification of the sperm epigenome. Sci Rep 6:31794CrossRefGoogle Scholar
  44. Rodgers AB, Morgan CP, Leu NA, Bale TL (2015) Transgenerational epigenetic programming via sperm microRNA recapitulates effects of paternal stress. Proc Natl Acad Sci USA 112:13699–13704CrossRefGoogle Scholar
  45. Rompala GR, Mounier A, Wolfe CM, Lin Q, Lefterov I, Homanics GE (2018) Heavy chronic intermittent ethanol exposure alters small noncoding RNAs in mouse sperm and epididymosomes. Front Genet 9:32CrossRefGoogle Scholar
  46. Sanchez-Vasquez E, Alata Jimenez N, Vazquez NA, Strobl-Mazzulla PH (2018) Emerging role of dynamic RNA modifications during animal development. Mech Dev. Google Scholar
  47. Schuster A, Skinner MK, Yan W (2016a) Ancestral vinclozolin exposure alters the epigenetic transgenerational inheritance of sperm small noncoding RNAs. Environ Epigenet 2(1):dvw001. CrossRefGoogle Scholar
  48. Schuster A, Tang C, Xie Y, Ortogero N, Yuan S, Yan W (2016b) SpermBase: a database for sperm-borne RNA contents. Biol Reprod 95:99CrossRefGoogle Scholar
  49. Sharma U, Conine CC, Shea JM, Boskovic A, Derr AG, Bing XY, Belleannee C, Kucukural A, Serra RW, Sun F, Song L, Carone BR, Ricci EP, Li XZ, Fauquier L, Moore MJ, Sullivan R, Mello CC, Garber M, Rando OJ (2016) Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals. Science 351:391–396CrossRefGoogle Scholar
  50. Shea JM, Serra RW, Carone BR, Shulha HP, Kucukural A, Ziller MJ, Vallaster MP, Gu H, Tapper AR, Gardner PD, Meissner A, Garber M, Rando OJ (2015) Genetic and epigenetic variation, but not diet, shape the sperm methylome. Dev Cell 35:750–758CrossRefGoogle Scholar
  51. Short AK, Yeshurun S, Powell R, Perreau VM, Fox A, Kim JH, Pang TY, Hannan AJ (2017) Exercise alters mouse sperm small noncoding RNAs and induces a transgenerational modification of male offspring conditioned fear and anxiety. Transl Psychiatry 7:e1114CrossRefGoogle Scholar
  52. Skinner MK (2011) Environmental epigenetic transgenerational inheritance and somatic epigenetic mitotic stability. Epigenetics 6:838–842CrossRefGoogle Scholar
  53. Soubry A, Hoyo C, Jirtle RL, Murphy SK (2014) A paternal environmental legacy: evidence for epigenetic inheritance through the male germ line. BioEssays 36:359–371CrossRefGoogle Scholar
  54. Soubry A, Guo L, Huang Z, Hoyo C, Romanus S, Price T, Murphy SK (2016) Obesity-related DNA methylation at imprinted genes in human sperm: results from the TIEGER study. Clin Epigenet 8:51CrossRefGoogle Scholar
  55. Tseng YT, Liao HF, Yu CY, Mo CF, Lin SP (2015) Epigenetic factors in the regulation of prospermatogonia and spermatogonial stem cells. Reproduction 150:R77–R91CrossRefGoogle Scholar
  56. Tuorto F, Liebers R, Musch T, Schaefer M, Hofmann S, Kellner S, Frye M, Helm M, Stoecklin G, Lyko F (2012) RNA cytosine methylation by Dnmt2 and NSun2 promotes tRNA stability and protein synthesis. Nat Struct Mol Biol 19:900–905CrossRefGoogle Scholar
  57. Wei Y, Yang CR, Wei YP, Zhao ZA, Hou Y, Schatten H, Sun QY (2014) Paternally induced transgenerational inheritance of susceptibility to diabetes in mammals. Proc Natl Acad Sci USA 111:1873–1878CrossRefGoogle Scholar
  58. Wei JW, Huang K, Yang C, Kang CS (2017) Non-coding RNAs as regulators in epigenetics (review). Oncol Rep 37:3–9CrossRefGoogle Scholar
  59. Youngson NA, Whitelaw E (2008) Transgenerational epigenetic effects. Annu Rev Genom Hum Genet 9:233–257CrossRefGoogle Scholar
  60. Yuan S, Schuster A, Tang C, Yu T, Ortogero N, Bao J, Zheng H, Yan W (2016) Sperm-borne miRNAs and endo-siRNAs are important for fertilization and preimplantation embryonic development. Development 143:635–647CrossRefGoogle Scholar
  61. Zhang Y, Zhang X, Shi J, Tuorto F, Li X, Liu Y, Liebers R, Zhang L, Qu Y, Qian J, Pahima M, Liu Y, Yan M, Cao Z, Lei X, Cao Y, Peng H, Liu S, Wang Y, Zheng H, Woolsey R, Quilici D, Zhai Q, Li L, Zhou T, Yan W, Lyko F, Zhang Y, Zhou Q, Duan E, Chen Q (2018) Dnmt2 mediates intergenerational transmission of paternally acquired metabolic disorders through sperm small non-coding RNAs. Nat Cell Biol 20:535–540CrossRefGoogle Scholar
  62. Zhu L, Liu X, Pu W, Peng Y (2018) tRNA-derived small non-coding RNAs in human disease. Cancer Lett 419:1–7CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of BiomedicineAarhus UniversityAarhus CDenmark

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