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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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Self-citationAn Aptitude for Altitude: Are Epigenomic Processes Involved?
Julian, C. G. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.01397 · Cited by 8
Park, S. H., Pan, J., Zhang, X., Lin, T.-A., Tang, S., Li, X., Cheloufi, S., Chen, Q., Zhou, T., & Zhou, C. (2025) · Journal of the Endocrine Society · doi:10.1210/jendso/bvaf214 · Cited by 9
“For instance, we previously reported that sperm contain abundant sncRNAs, especially tsRNAs and rsRNAs, which play a significant role in regulating intergenerational inheritance of paternally acquired metabolic disorders (40, 43, 44, 52, 53, 120).”
InfluentialSelf-citationZhou, Q., He, M., Liu, M., Sun, G., & Li, J. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1698265 · Cited by 6
Self-citationPUS10-induced tRNA fragmentation impacts retrotransposon-driven inflammation
Madej, M., Ngoc, P. C. T., Muthukumar, S., Konturek-Cieśla, A., Tucciarone, S., Germanos, A. A., Ashworth, C., Kotarsky, K., Ghosh, S., Fan, Z., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.115735 · Cited by 7
tRNA-derived small RNAs (tsRNAs): establishing their dominance in the regulation of human cancer
Gong, L., Hu, Y., Pan, L., & Cheng, Y. (2024) · Frontiers in Genetics · doi:10.3389/fgene.2024.1466213 · Cited by 6
The Sperm Small RNA Transcriptome: Implications beyond Reproductive Disorder
Chan, S. Y., Wan, C. W. T., Law, T. Y. S., Chan, D. Y. L., & Fok, K. L. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232415716 · Cited by 12
“[98], where the deletion of tRNA methyltransferase (Dmnt2) abolished the m5C and m2G modifications in their HFD sperm tsRNAs, as well as the metabolic disorders in the subsequent offspring of Dmnt2−/− HFD sires.”
BackgroundThe non-coding genome in early human development – Recent advancements
Paloviita, P., & Vuoristo, S. (2022) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2022.02.010 · Cited by 12
Effect of Nano-SiO2 on Expression and Aberrant Methylation of Imprinted Genes in Lung and Testis
Yuan, B.-L., Zhang, H.-Z., Wang, X., Pan, Y., & Jiang, J.-C. (2018) · Nanoscale Research Letters · doi:10.1186/s11671-018-2673-4 · Cited by 7
In Search of Darwin's Imaginary Gemmules
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Self-citationEpididymis-specific RNase A family genes regulate fertility and small RNA processing
Shaffer, J. F., Gupta, A., Kharkwal, G., Linares, E. E., Holmes, A., Swartz, J. R., Katzman, S. J., & Sharma, U. (2024) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2024.107933 · Cited by 13
“Moreover, loss of DNMT2 leads to alterations of sperm tRF and rsRNA levels, potentially via altering the modi fi cation status on these RNAs (82).”
Wu, S., Xie, H., Yao, S., Jia, X., Mi, Y., Jia, Y., & Ying, H. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1205408 · Cited by 6
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“elegans physiology, including processes such as chemosensation and longevity.(53,54) Likewise, small RNAs from theC.”
BackgroundGenetic control of non-genetic inheritance in mammals: state-of-the-art and perspectives
Tomar, A., & Teperino, R. (2020) · Mammalian Genome · doi:10.1007/s00335-020-09841-5 · Cited by 6
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“…sperm RNA extracts or specific subsets of sperm small noncoding RNAs (sncRNAs), such as microRNAs (miRNAs) and tRNA-derived small RNAs (tsRNAs), have established causal evidence that the “sperm RNA code” mediates the transmission of environmental stresses from fathers to offspring (4, 11 – 19 ).”
CryoEM structure of the SLFN14 endoribonuclease reveals insight into RNA binding and cleavage
Riper, J. M. V., Martinez-Claros, A. O., Wang, L., Schneiderman, H. E., Maheshwari, S., & Pillon, M. C. (2025) · Nature Communications · doi:10.1038/s41467-025-61091-8 · Cited by 7
Epididymal-Born circRNA Cargo and Its Implications in Male Fertility
Manfrevola, F., Mosca, N., Mele, V. G., Chioccarelli, T., Migliaccio, A., Mattia, M., Pezzullo, M., Cobellis, G., Potenza, N., & Chianese, R. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26062614 · Cited by 8
“Indeed, an unbalanced paternal diet increases the incidence of metabolic disorders in the offspring, whereas paternal stress can affect offspring behavioral development [92–97].”
Insight into noncanonical small noncoding RNAs in Influenza A virus infection
Ko, E., Zhou, T., & Ko, J. (2024) · Virus Research · doi:10.1016/j.virusres.2024.199474 · Cited by 5
“Noncanonical sncRNAs, alongside the harbored RNA modifications, potentially serve as carriers of epigenetic information and play a substantial role in transgenerational/intergenerational epigenetic inheritance (Chen et al., 2016; Liu et al., 2023; Zhang et al., 2018).”
Self-citationLiu, S., Holmes, A. D., Katzman, S., & Sharma, U. (2024) · bioRxiv · doi:10.1101/2024.08.08.607197 · Cited by 5
“Consistent with these observations, histone genes were overall upregulated in Val_LNA embryos compared to all other genes ( Figure 2F ). tRFs carry modified residues important for their stability and function [13, 53, 54].”
ResultSelf-citationInheritance of Stress Responses via Small Non-Coding RNAs in Invertebrates and Mammals
Ow, M. C., & Hall, S. E. (2023) · Epigenomes · doi:10.3390/epigenomes8010001 · Cited by 8
“Indeed, deletion of the tRNA methyltransferase, DNMT2, abolished the inheritance of metabolic phenotypes from high-fat-diet males [229].”
BackgroundtRNA-derived fragments: mechanism of gene regulation and clinical application in lung cancer
Wu, F., Yang, Q., Pan, W., Wei, M., Ma, Z., & Wang, W. (2023) · Cellular Oncology · doi:10.1007/s13402-023-00864-z · Cited by 5
“Each type of tRF can only be cleaved by the corresponding RNase and has potential biological value [9, 10].”
Unravelling Strain-Specific Modifications of Toxoplasma gondii tRNA and sncRNA Using LC-MS/MS
Wang, W., Yang, Y., Guo, H., Li, M.-H., Chen, X.-Q., Wei, X.-Y., Chen, Y., Elsheikha, H., & Zhang, X.-X. (2023) · Microbiology spectrum · doi:10.1128/spectrum.03564-22 · Cited by 5
Self-citationStress‐sensitive dynamics of miRNAs and Elba1 in Drosophila embryogenesis
Örkenby, L., Skog, S., Ekman, H., Gozzo, A., Kugelberg, U. Ö., Ramesh, R., Magadi, S. S., Zambanini, G., Nordin, A., Cantù, C., et al. (2023) · Molecular Systems Biology · doi:10.15252/msb.202211148 · Cited by 8
Maternal Prepregnancy 5-Hydroxytryptamine Exposure Affects the Early Development of the Fetus
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Self-citationMLC Seq: De novo sequencing of full-length tRNA isoforms by mass ladder complementation
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Self-citationThe role of non-genetic information in evolutionary frameworks
Moran, K. L., Shlyakhtina, Y., & Portal, M. M. (2021) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2021.1908949 · Cited by 7
“In that regard, it is thought that this could enable the encoding of information, via a diverse array of RNA types and their modifications, that can subsequently be inherited and decoded during offspring development (Zhang et al. 2018).”
BackgroundA mechanism of inheritance of acquired traits in animals
Cabej, N. R. (2021) · Developmental Biology · doi:10.1016/j.ydbio.2021.03.004 · Cited by 7
Identification, expression, and artificial selection of silkworm epigenetic modification enzymes
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Self-citationSperm Originated Chromatin Imprints and LincRNAs in Organismal Development and Cancer
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tRNA-Derived Small RNAs: The Good, the Bad and the Ugly
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Ignoring the planet: A critical blind spot for research on ageing
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“Animal models demonstrate that paternal OS exposure induces behavioral abnormalities, altered stress responses, and metabolic dysregulation in F1 and F2 generations through sperm RNA-mediated epigenetic inheritance [123,138].”
NSUN7 is a catalytically inactive RNA m5C methyltransferase essential for sperm flagellum assembly
Li, J., Zhu, W., Wang, Z., Zhang, Y., Hua, M.-M., Liu, Q.-Y., Zhou, Y.-J., Wu, X., Li, H., Liu, M., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-67233-2 · Cited by 4
Self-citationPANDORA-seq reveals human sperm sncRNA signature endowed with sperm quality assessment
Huang, R., Yang, Y., Jiang, W., Cao, Z., Shi, J., Zhang, X.-O., & Zhang, Y. (2025) · Genes & Diseases · doi:10.1016/j.gendis.2025.101807 · Cited by 4
“14,17 24 Likewise, rsRNAs are classified by their derivation from different rRNA origins, such as 5S, 5.8S, 18S, and 28S rsRNAs.”
Self-citationThe multifaceted role of m5C RNA methylation in digestive system tumorigenesis
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“DNMT2, initially identi fi ed as a DNA methyltransferase, was later recognized for its role in catalyzing m5C modi fi cations in tRNA as well (Cheng et al., 2018; Li H. et al., 2024; Zhang et al., 2018).”
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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