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Dnmt2 mediates intergenerational transmission of paternally acquired metabolic disorders through sperm small non-coding RNAs
Open accessAbstract
The discovery of RNAs (for example, messenger RNAs, non-coding RNAs) in sperm has opened the possibility that sperm may function by delivering additional paternal information aside from solely providing the DNA 1 . Increasing evidence now suggests that sperm small non-coding RNAs (sncRNAs) can mediate intergenerational transmission of paternally acquired phenotypes, including mental stress 2,3 and metabolic disorders 4-6. How sperm sncRNAs encode paternal information remains unclear, but the mechanism may involve RNA modifications. Here we show that deletion of a mouse tRNA methyltransferase, DNMT2, abolished sperm sncRNA-mediated transmission of high-fat-diet-induced metabolic disorders to offspring. Dnmt2 deletion prevented the elevation of RNA modifications (m 5 C, m 2 G) in sperm 30-40 nt RNA fractions that are induced by a high-fat diet. Also, Dnmt2 deletion altered the sperm small RNA expression profile, including levels of tRNA-derived small RNAs and rRNA-derived small RNAs, which might be essential in composing a sperm RNA 'coding signature' that is needed for paternal epigenetic memory. Finally, we show that Dnmt2-mediated m 5 C contributes to the secondary structure and biological properties of sncRNAs, implicating sperm RNA modifications as an additional layer of paternal hereditary information.
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“it has since been discovered that sperm‐derived mtRNA can respond to environmental cues and affect subsequent offspring development and health trajectories [34, 35, 36, 37].”
From Ignoring the planet: A critical blind spot for research on ageing (2025) · cites this paper as [36]
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“…2023; Li et al, 2025b), sperm quality and epigenetic inheritance (Alata Jimenez et al, 2023; Cai and Chen, 2024; Chen et al, 2016a; Chen et al, 2016b; Isacson et al, 2025; Natt et al, 2019; Sharma et al, 2016; Shi et al, 2026; Tomar et al, 2024; Zhang et al, 2018), and symbiosis (Ren et al, 2019).”
Self-citationtRNA methylation: functional insights and epitranscriptomic regulation
Wang, S., Yan, W., Zhao, T., Ma, B., Chen, S., Chen, L., Niu, L., Zhao, Y., Gan, M., Zhu, L., et al. (2026) · Cell Communication and Signaling · doi:10.1186/s12964-026-03005-9
“Deletion of DNMT2 reduces m 5 C abundance on tsRNAs, decreases their stability, and prevents sperm tsRNAs from transmitting high-fat-diet-induced metabolic disorders to offspring [35].”
Self-citationDynamic tRNA modification landscapes reveal METTL1 in fibroblasts as a central regulator of aging
Zhu, Y., Wang, X., Li, Y., Jiang, W., Wu, Z., Xu, S., Tan, Z., Wu, A., Cai, Y., Yang, Y., et al. (2026) · Science China Life Sciences · doi:10.1007/s11427-025-3287-6
Self-citationc-FLIP: A pseudoprotease with emerging metal-binding activity.
DSouza, R. S., Nakasone, Y., Iwabe, N., Tomii, K., Suzuki, J., & Sakamaki, K. (2026) · The FEBS Journal · doi:10.1111/febs.70593
Maternal obesity and offspring neurodevelopment: Mechanisms, risks, and prevention opportunities
Djamalutdinova, I., Ibragimovich, T. K., Kholikov, A., Àbdullaev, D., & Ruziyeva, G. (2026) · Developmental Dynamics · doi:10.1002/dvdy.70146
tRNA-derived small RNAs in ocular neovascular diseases: A systematic review
Liu, T., Kuai, P.-Z., Luo, Y.-S., Song, Y., Wang, Y., Huang, X.-B., & Cao, X. (2026) · Non-coding RNA Research · doi:10.1016/j.ncrna.2026.03.004
“DNMT2-and NSUN2-mediated m 5 C modifications increase tRNA stability, and their deficiency renders tRNAs more susceptible to cleavage into tsRNAs [24].”
Self-citationA Combinatorial Model of Serum tsRNAs as a Diagnostic Biomarker for Non‐Small Cell Lung Cancer
Hu, X., Yang, X., Jin, P., Tian, J., Tao, C., Tang, Y., & Zhang, Y. (2026) · Molecular Carcinogenesis · doi:10.1002/mc.70124
Self-citationGlobal research trends on the impact of obesity on male infertility: a bibliometric analysis
Wang, J., Huang, W., Tan, M., Xu, N., He, Q., & Sun, G. (2026) · Frontiers in Nutrition · doi:10.3389/fnut.2026.1817082
“At the RNA level, sperm small non-coding RNAs serve as key carriers of metabolic information (35, 36).”
Zu, B., Zhang, Y., Yu, Z., Li, B., Cheng, S., Du, M., Li, R., Liu, C., & Zhou, B. (2026) · Environmental Science & Technology · doi:10.1021/acs.est.6c00486 · Cited by 2
Self-citationYing, Z.-K., Xu, X.-Y., Hu, J., Cui, Y., & Jiang, D.-W. (2026) · World Journal of Stem Cells · doi:10.4252/wjsc.v18.i3.118401
Galambos, N., Crocker, O. J., Schneider, B. K., Allerton, K. S., Gross, K. E., Schneider, A. E., Lynch, J., Yukselen, O., Küçükural, A., & Conine, C. C. (2026) · Nature Communications · doi:10.1038/s41467-026-70029-7 · Cited by 4
“In mammals, tDRs, particularly tDR-Gly-GCC, were shown to be regulated by paternal diet and to transmit non-genetically inherited phenotypes to offspring, including altered embryonic gene expression and adult metabolism 4 – 6 .”
Lee, E., Choi, S. Y., Song, S. M., Lindroth, A. M., & Park, Y. J. (2026) · Molecular Metabolism · doi:10.1016/j.molmet.2026.102350
“The absence of the tRNA methyltransferase DNMT2 resulted in increased tRFs that did not function as mediators of the intergenerational effect [38].”
InfluentialRNA modifications: disease biomarkers and signaling molecules.
Pan, S., Zhang, L., Zhang, Y.-F., Shi, J.-C., & Zhang, Y. (2026) · Trends in endocrinology and metabolism · doi:10.1016/j.tem.2026.01.004
Self-citationDing, H., Zhang, Y., Wang, B., Li, Y., Zhao, X., & Ge, P. (2026) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2026.150350
Self-citationChadwick, H., Bambini-Júnior, V., Dawson, N., & Hawkes, C. A. (2025) · Obesity Reviews · doi:10.1111/obr.70067
“Moreover, deletion of the tRNA methyltransferase DNMT2 alters levels of tsR-NAs in the sperm and prevents paternal HF-induced metabolic dysfunction in mouse offspring [199].”
Lei, J., Zhao, M., Yao, S., Lu, M., Deng, F., Xu, T., Zhang, M., Sun, M., & Gao, Q. (2025) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.125.323061
Sperm non-coding RNAs and pregnancy outcomes: A literature review
Dolati, P., Esmaeilzadeh, E., & Khorshid, H. (2025) · Gene Reports · doi:10.1016/j.genrep.2025.102420
Zhu, C., Peng, G., Liu, Q., Wang, X., Sun, C., Zhu, H., Ding, Y., Liu, S., Yang, F., Chen, Z., et al. (2025) · Comparative Biochemistry and Physiology Part D Genomics and Proteomics · doi:10.1016/j.cbd.2025.101644
Self-citationChen, Y., Sun, T.-T., Yuan, P.-H., & Liu, C. (2025) · Journal of Assisted Reproduction and Genetics · doi:10.1007/s10815-025-03470-0
“Moreover, mental stress serves as an important epigenetic factor that affects the phenotype of offspring through transgenerational inheritance, especially via sperm non-coding RNAs [6, 12, 13].”
NOVEL CHARACTERISTICS OF SMALL NONCODING RNAS IN RAT EPIDIDYMAL EXTRACELLULAR PARTICLESPreprint
Gillette, R., Sheinhaus, D. L., Waghwala, S., & Gore, A. C. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.05.27.493742
“This method has been used to demonstrate inter-or transgenerational inheritance of metabolic [27,30,92] and behavioral phenotypes [93–95].”
Mendes, R. S. (2024) · Cosmological and Astrobiological Review Journal for the Study of the Universe Life and the Natural Sciences · doi:10.65932/car-2024-1-5 · Cited by 1
Khdc3 Regulates Metabolism Across Generations in a DNA-Independent MannerPreprint
Senaldi, L., Hassan, N. A., Cullen, S. M., Balaji, U., Trigg, N. A., Gu, J., Finkelstein, H., Phillips, K. L., Conine, C. C., & Smith-Raska, M. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.02.27.582278
“Some of the genes associated with genetic nurture act by altering the expression of RNAs in the gamete, which can affect processes such as glucose metabolism and body weight (16).”
Maternal enzyme reprograms paternal DNA for healthy offspring
Kawamura, Y. K., & Peters, A. H. F. M. (2022) · Nature · doi:10.1038/d41586-022-01237-6
Neither Dogmas nor Barriers are Absolute
Noble, D. (2022) · Biosemiotics · doi:10.1007/s12304-022-09475-x
“A good example is the work of Zhang et al. (2018) showing the nucleotides that transmit paternally-acquired metabolic disorders.”
BackgroundÖrkenby, L., Skog, S., Ekman, H., Kugelberg, U. Ö., Ramesh, R., Roth, M. G. L., Nätt, D., & Öst, A. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.10.27.466124
“…with other small non-coding RNAs (sncRNAs), including piRNA, fragments of tRNA (tsRNA), and rRNA (rsRNA), play important roles in inter- and transgenerational epigenetic inheritance (de Castro Barbosa et al., 2015; Grandjean et al., 2015; Nätt et al., 2019; Sharma et al., 2016; Zhang et al., 2018).”
BackgroundMaternal transmission of a paramutant phenotype requires intact DNMT2 functions in the male germline
Yu, T., Xie, Y., Tang, C., Wang, Y., Yuan, S.-Q., Zheng, H., & Yan, W. (2020) · bioRxiv · doi:10.1101/2020.10.22.351155
“The data indicate that Dnmt2 inactivation in male mice can block, to a 93 large extend, the paternal/sperm-mediated transmission of acquired phenotypes, including 94 the while tails in Kit paramutant mice and HFD-induced metabolic disorders (12, 13).”
BackgroundMethodSelf-citationEpigenetics Mechanisms in Insects: A Review
Pirithiraj, U., Soundararajan, R., & Justin, C. (2020) · doi:10.20546/ijcmas.2020.905.339
“Histone ubiquitination is a modification mediated by the attachment of ubiquitin (Ub), which is a 76-amino acid protein that is ubiquitously distributed and highly conserved throughout eukaryotic organisms (Kerscher et al., 2006; Zhang et al., 2018).”
The expanding repertoire of hereditary information carriers
Zhang, Y., & Chen, Q. (2019) · Development · doi:10.1242/dev.170902 · Cited by 16
“dietinduced metabolic disorders, stress-induced behavioral changes (Chen et al., 2016a; Gapp et al., 2014; Gapp et al., 2018; Grandjean et al., 2015; Öst et al., 2014; Rechavi et al., 2014; Sharma et al., 2016; Zhang et al., 2018).”
InfluentialSelf-citationContrôle de l’expression des gènes par les micro-ARN nucléaires : étude des mécanismes moléculaires
Matégot, R. (2018) · theses.fr (ABES) · doi:10.70675/959c6c45z7b7ez4353zac7eze717c4dba02a
Maintenance and change of phenotype: Inheritance of acquired traits
Cabej, N. R. (2021) · Elsevier eBooks · doi:10.1016/b978-0-323-85154-1.00002-3
Future Perspectives in Epigenetic Inheritance
Darr, J. (2020) · Springer eBooks · doi:10.1007/978-3-030-35213-4_12 · Cited by 1
The paternal diet regulates the offspring epigenome and health
Yan, M. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-816843-1.00012-6
Self-citationDarwin's Pangenesis and the Lamarckian Inheritance of Acquired Characters
Liu, Y. (2018) · Advances in genetics · doi:10.1016/bs.adgen.2018.05.005 · Cited by 1
Self-citation
Metadata
- Authors
- 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.
- Affiliations
- University of Nevada, Reno (US)
- German Cancer Research Center (DE)
- Chinese Academy of Sciences (CN)
- Shandong University of Technology (CN)
- Corresponding author
- Zhang, Ying
- Zhou, Qi
- Duan, Enkui
- Chen, Qi
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2018-04-25
- Volume
- 20
- Issue
- 5
- Pages
- 535-540
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC5926820
- OpenAlex
- W2802402149
- Cited by
- 468
- References
- 50
- Citations by year
- 2026: 43 · 2025: 59 · 2024: 50 · 2023: 67 · 2022: 68 · 2021: 56 · 2020: 62 · 2019: 40 · 2018: 22
- FWCI
- 16.72
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute of General Medical Sciences (P30GM110767, P20GM103440)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD060858, R01HD085506, R01HD092431)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
- Keywords
- DNMT2, intergenerational transmission, tRNA-derived small RNAs, rRNA-derived small RNAs, RNA methylation, 5-methylcytosine, high-fat diet, sperm epigenome
- MeSH terms
- Paternal Inheritance, Animals, Blood Glucose, DNA (Cytosine-5-)-Methyltransferases, Insulin, Male, Mice, Inbred C57BL, Nucleic Acid Conformation, Phenotype, Spermatozoa, Structure-Activity Relationship, Biomarkers, Mice, Knockout, Gene Expression Regulation, Developmental, Genetic Predisposition to Disease, Heredity, NIH 3T3 Cells, Epigenesis, Genetic, Glucose Metabolism Disorders, Mice, RNA, Small Untranslated, Diet, High-Fat, Transcriptome, Gene-Environment Interaction
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