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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Sperm-derived mtRNA can respond to environmental cues and affect subsequent offspring development and health trajectories.
“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]
The Main text reports that a paternal high-fat diet changes sperm small-RNA profiles and that sperm RNA can transmit metabolic effects to mouse offspring. It discusses tRNA-derived small RNAs and other small non-coding RNAs, but does not identify the responsible RNA as mitochondrial RNA (mtRNA). (LLM, conf=0.86)
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“Furthermore, deletion of DNMT2/TRDMT1, a (cytosine-5) tRNA methyltransferase, abolished sperm-mediated transmission of HFD-induced metabolic disorders into offspring [172] indicating that m5C contributed to biological properties of tsRNAs.”
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“Similarly, recent studies found that mammalian Nsun2- and Dnmt2-mediated m(5)C in tRNAs can profoundly affect tsRNA biogenesis [12–14] and the structure of the resulting tsRNAs [14], suggesting tsRNA-mediated translational control in stem cell function, embryo development, and intergenerational epigenetic inheritance…”
Self-citationRNA 5-methylcytosine modification and its emerging role as an epitranscriptomic mark
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“…that this may be related to the spectrum of sperm sncRNAs and associated RNA modifications; the loss of RNA methyl-transferase DNMT2 leads to hypomethylation of m5C, promoting tRNA fragmentation, altering the biological properties of tsRNAs and thus affecting the phenotype of the offspring [64].”
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“We further showed that RNA modifications can alter secondary sncRNA structures and biological properties and are required for sperm sncRNAs’ biological impact in epigenetic inheritance (Zhang et al., 2018).”
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Self-citationNovel insights into the emerging roles of tRNA-derived fragments in mammalian development
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“This study further revealed that Dnmt2-mediated m(5)C affected the secondary structure and biological properties of abundant 3ʹtRFs upon transfection in cell lines [46], although the exact contribution of m(5)C for tRF-mediated paternal inheritance was not fully delineated.”
BackgroundInfluentialTransgenerational epigenetic inheritance: from phenomena to molecular mechanisms
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“Offspring produced from oocytes injected with RNA from Dnmt2 KO sperm showed reduced phenotypes associated with high-fat-dietinduced metabolic disorders [258].”
BackgroundMultigenerational epigenetic inheritance: One step forward, two generations back
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“demonstrated that a methyltransferase, DNMT2, mediated paternal HFD-induced metabolic disorder transmission by altering the sperm tsRNA expression profile (72).”
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“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).”
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Self-citationTHUMPD3–TRMT112 is a m2G methyltransferase working on a broad range of tRNA substrates
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“In addition, tRNA modifications are related to the generation of tRNA-derived fragments (tRFs) (9), immune responses (10), homeostasis (11) and intergenerational inheritance (12).”
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“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…”
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“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].”
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The emerging impact of tRNA modifications in the brain and nervous system
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“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
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“DNMT2 deletion changes the expression profile of sperm small RNAs, indicating indirectly that RNA modifications have a significant impact on germline development [90,91].”
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“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
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A comprehensive overview of bull sperm-borne small non-coding RNAs and their diversity across breeds
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RNA m5C modification: from physiology to pathology and its biological significance
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Self-citationPosition 34 of tRNA is a discriminative element for m5C38 modification by human DNMT2
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“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
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Production and purification of endogenously modified tRNA-derived small RNAs
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“[70,71] raises the question as to which RNAs exactly contribute to these processes.”
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Epitranscriptomic 5-Methylcytosine Profile in PM2.5-induced Mouse Pulmonary Fibrosis
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tsRNA modifications: An emerging layer of biological regulation in disease
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“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 38 · see citing works
Self-citationEpitranscriptomics in metabolic disease
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- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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