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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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Jia, Y., Tan, W., & Zhou, Y. (2020) · Annals of Translational Medicine · doi:10.21037/atm-20-2797 · Cited by 72
“demonstrated that a methyltransferase, DNMT2, mediated paternal HFD-induced metabolic disorder transmission by altering the sperm tsRNA expression profile (72).”
BackgroundChen, X., Zheng, Y., Lei, A., Zhang, H., Niu, H., Li, X., Zhang, P., Liao, M., Lv, Y., Zhu, Z., et al. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.013003 · Cited by 78
“Sperm tsRNAs carry paternal epigenetic information and could act as acquired epigenetic factors that influence offspring phenotypes in response to environmental stress (9, 12, 13).”
BackgroundMethodSelf-citationZhang, Q., Zheng, Q., Yu, X., He, Y., & Guo, W. (2020) · Journal of Translational Medicine · doi:10.1186/s12967-020-02417-6 · Cited by 65
Yoshida, K., Maekawa, T., Ly, N. H., Fujita, S.-I., Muratani, M., Ando, M., Katou, Y., Araki, H., Miura, F., Shirahige, K., et al. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.02.028 · Cited by 82
Emerging functional principles of tRNA-derived small RNAs and other regulatory small RNAs
Chen, Q., & Zhou, T. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.105225 · Cited by 70
Self-citationTHUMPD3–TRMT112 is a m2G methyltransferase working on a broad range of tRNA substrates
Yang, W., Xiong, Q., Ge, J., Li, H., Zhu, W., Nie, Y., Lin, X., Lv, D., Li, J., Lin, H., et al. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab927 · Cited by 66
“In addition, tRNA modifications are related to the generation of tRNA-derived fragments (tRFs) (9), immune responses (10), homeostasis (11) and intergenerational inheritance (12).”
BackgroundChioccarelli, T., Pierantoni, R., Manfrevola, F., Porreca, V., Fasano, S., Chianese, R., & Cobellis, G. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9030640 · Cited by 68
“rsRNAs Mature SPZ are enriched in rsRNAs [50] rsRNAs are considered sperm quality biomarkers [49] Small RNA profiles in ejaculated sperm, epididymal sperm and seminal plasma indicate that sperm RNAs may have origins other than the testes [79] The deletion of a mouse tRNA methyltransferase, DNMT2, abolisheds sperm sncR…”
BackgroundEpigenetic regulations in mammalian spermatogenesis: RNA-m6A modification and beyond
Gui, Y., & Yuan, S. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-03823-9 · Cited by 73
“Further studies showed that deletion of tRNA methyltransferase abolished the transmission of HFD-induced metabolic disorder, implicating sperm RNA modifications as an additional layer of paternal hereditary information [84].”
BackgroundNutrition and its role in epigenetic inheritance of obesity and diabetes across generations
Kaspar, D., Hastreiter, S., Irmler, M., de Angelis, M. H., & Beckers, J. (2020) · Mammalian Genome · doi:10.1007/s00335-020-09839-z · Cited by 87
Diet-Induced Modification of the Sperm Epigenome Programs Metabolism and Behavior
Bodden, C., Hannan, A. J., & Reichelt, A. C. (2019) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2019.10.005 · Cited by 81
Rompala, G. R., & Homanics, G. E. (2019) · Alcoholism Clinical and Experimental Research · doi:10.1111/acer.14029 · Cited by 70
Emerging roles of tRNA-derived small RNAs in cancer biology
Lee, S. B., Kim, J., Valdmanis, P. N., & Kim, H. K. (2023) · Experimental & Molecular Medicine · doi:10.1038/s12276-023-01038-5 · Cited by 61
The emerging impact of tRNA modifications in the brain and nervous system
Ramos, J., & Fu, D. (2018) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2018.11.007 · Cited by 60
Zhu, L., Marjani, S. L., & Jiang, Z. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.557934 · Cited by 62
“In addition, several RNA modifications such as m5C, m2G have been found to be enriched in the sperm tsRNA and are sensitive to diet changes (Chen et al., 2016a; Zhang et al., 2018).”
BackgroundtRNA-Derived Small RNAs and Their Potential Roles in Cardiac Hypertrophy
Cao, J., Cowan, D. B., & Wang, D. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.572941 · Cited by 60
The influence of paternal diet on sncRNA-mediated epigenetic inheritance
Klastrup, L. K., Bak, S. T., & Nielsen, A. L. (2018) · Molecular Genetics and Genomics · doi:10.1007/s00438-018-1492-8 · Cited by 66
Zhou, W., Wang, X., Chang, J., Cheng, C., & Miao, C. (2021) · Critical Reviews in Clinical Laboratory Sciences · doi:10.1080/10408363.2021.2002256 · Cited by 58
“DNMT2 deletion changes the expression profile of sperm small RNAs, indicating indirectly that RNA modifications have a significant impact on germline development [90,91].”
BackgroundZhou, W., Wang, C., Chang, J., Huang, Y., Xue, Q., Miao, C., & Wu, P. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.722728 · Cited by 46
Zhao, P., Lin, X., Chen, D., Xu, W., Guo, H., Xu, Y., Yan, B., Wu, X., Li, Y., Zhang, Y., et al. (2024) · Experimental Hematology and Oncology · doi:10.1186/s40164-024-00477-8 · Cited by 49
“Northern blotting was performed as previously described [37].”
MethodSelf-citationSu, Z., Frost, E. L., Lammert, C. R., Przanowska, R. K., Lukens, J. R., & Dutta, A. (2019) · bioRxiv · doi:10.1101/2019.12.20.884650 · Cited by 47
“9 half stability [81-86], it will be interesting to examine how each factor contributes to the regulation observed in the maternal-fetal interface.”
BackgroundHijacking tRNAs From Translation: Regulatory Functions of tRNAs in Mammalian Cell Physiology
Avcilar-Kücükgöze, I., & Kashina, A. S. (2020) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2020.610617 · Cited by 56
A comprehensive overview of bull sperm-borne small non-coding RNAs and their diversity across breeds
Sellem, E., Marthey, S., Rau, A., Jouneau, L., Allais‐Bonnet, A., Perrier, J., Fritz, S., Danvic, C. L., Boussaha, M., Kiefer, H., et al. (2020) · Epigenetics & Chromatin · doi:10.1186/s13072-020-00340-0 · Cited by 70
RNA m5C modification: from physiology to pathology and its biological significance
Chen, X., Yuan, Y., Zhou, F., Huang, X., Li, L., Pu, J., Zeng, Y., & Jiang, X. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1599305 · Cited by 37
Self-citationPosition 34 of tRNA is a discriminative element for m5C38 modification by human DNMT2
Huang, Z., Li, J., Xiong, Q., Li, H., Wang, E., & Liu, R. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab1148 · Cited by 45
“Dnmt2 could alter the sperm tsRNA expression profile, and mediate the transgenerational inheritance of paternal metabolic disorders to offspring through the m5C modification on sperm tsRNAs (16,32).”
Male reproductive health and intergenerational metabolic responses from a small RNA perspective
Nätt, D., & Öst, A. (2020) · Journal of Internal Medicine · doi:10.1111/joim.13096 · Cited by 46
Production and purification of endogenously modified tRNA-derived small RNAs
Drino, A., Oberbauer, V., Troger, C., Janisiw, E., Anrather, D., Hartl, M., Kaiser, S., Kellner, S. M., & Schaefer, M. (2020) · RNA Biology · doi:10.1080/15476286.2020.1733798 · Cited by 47
“[70,71] raises the question as to which RNAs exactly contribute to these processes.”
BackgroundYing, X., Hu, W., Huang, Y.-P., Lv, Y., Ji, D., Chen, C., Yang, B., Zhang, C., Liang, Y., Zhang, H.-Q., et al. (2024) · Advancement of science · doi:10.1002/advs.202400115 · Cited by 41
Epitranscriptomic 5-Methylcytosine Profile in PM2.5-Induced Mouse Pulmonary Fibrosis
Han, X., Liu, H., Zhang, Z., Yang, W., Wu, C., Liu, X., Zhang, F., Sun, B., Zhao, Y., Jiang, G., et al. (2020) · Genomics Proteomics & Bioinformatics · doi:10.1016/j.gpb.2019.11.005 · Cited by 42
Jehn, J., Treml, J., Wulsch, S., Ottum, B., Erb, V., Hewel, C., Kooijmans, R. N., Wester, L. E., Fast, I., & Rosenkranz, D. (2019) · bioRxiv · doi:10.1101/774380 · Cited by 39
tsRNA modifications: An emerging layer of biological regulation in disease
Liang, Y., Ji, D., Ying, X., Ma, R., & Ji, W. (2024) · Journal of Advanced Research · doi:10.1016/j.jare.2024.09.010 · Cited by 40
“Evidence reveals that m 5 C-tsRNA is critical to the epigenetic inheritance of paternal traits [102].”
InfluentialXiong, Y.-W., Zhu, H.-L., Zhang, J., Geng, H., Tan, L., Zheng, X., Li, H., Fan, L.-L., Wang, X., Zhang, X.-D., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-45675-4 · Cited by 39
Self-citationEpitranscriptomics in metabolic disease
Matsumura, Y., Wei, F., & Sakai, J. (2023) · Nature Metabolism · doi:10.1038/s42255-023-00764-4 · Cited by 55
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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