Intergenerational transport of double-stranded RNA in C. elegans can limit heritable epigenetic changes
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Abstract
RNAs in circulation carry sequence-specific regulatory information between cells in plant, animal, and host-pathogen systems. Such RNA can cross generational boundaries, as evidenced by somatic double-stranded RNA (dsRNA) in the nematode Caenorhabditis elegans silencing genes of matching sequence in progeny. Here we dissect the intergenerational path taken by dsRNA from parental circulation and discover that cytosolic import through the dsRNA importer SID-1 in the parental germline and/or developing progeny varies with developmental time and dsRNA substrates. Loss of SID-1 enhances initiation of heritable RNA silencing within the germline and causes changes in the expression of the s id-1 - d ependent g ene sdg-1 that last for more than 100 generations after restoration of SID-1. The SDG-1 protein is enriched in perinuclear germ granules required for heritable RNA silencing but is expressed from a retrotransposon targeted by such silencing. This auto-inhibitory loop suggests how retrotransposons could persist by hosting genes that regulate their own silencing.
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The Caenorhabditis elegans Argonautes ALG-1 and ALG-2: Almost Identical yet DifferentPreprint
Tops, B. B. J., Plasterk, R. H. A., & Ketting, R. F. (2006) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2006.71.035 · Cited by 41 · see citing works
Extracellular RNA in Central Nervous System Pathologies
Tielking, K., Fischer, S., Preissner, K. T., Vajkoczy, P., & Xu, R. (2019) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2019.00254 · Cited by 41 · see citing works
Mating can initiate stable RNA silencing that overcomes epigenetic recovery
Devanapally, S., Raman, P., Chey, M. S., Allgood, S. C., Ettefa, F., Diop, M., Lin, Y., Cho, Y. E., & Jose, A. M. (2021) · Nature Communications · doi:10.1038/s41467-021-24053-4 · Cited by 41 · see citing works
Self-citationCrane, M. M., Sands, B., Battaglia, C., Johnson, B., Yun, S. R., Kaeberlein, M. R., Brent, R., & Mendenhall, A. (2019) · Scientific Reports · doi:10.1038/s41598-019-45517-0 · Cited by 40 · see citing works
Price, I. F., Hertz, H. L., Pastore, B., Wagner, J., & Tang, W. (2021) · eLife · doi:10.7554/elife.72276 · Cited by 40 · see citing works
The use of fluorescent marker dyes for studying intercellular communication in nematode embryos
Bossinger, O., & Schierenberg, E. (1996) · The International Journal of Developmental Biology · doi:10.1387/ijdb.8735958 · Cited by 37 · see citing works
AMPK regulates germline stem cell quiescence and integrity through an endogenous small RNA pathway
Kadekar, P., & Roy, R. (2019) · PLoS Biology · doi:10.1371/journal.pbio.3000309 · Cited by 35 · see citing works
FDA approves fifth RNAi drug — Alnylam’s next-gen hATTR treatment
Mullard, A. (2022) · Nature Reviews Drug Discovery · doi:10.1038/d41573-022-00118-x · Cited by 35 · see citing works
Ow, M. C., Borziak, K., Nichitean, A. M., Dorus, S., & Hall, S. E. (2018) · PLoS Genetics · doi:10.1371/journal.pgen.1007219 · Cited by 34 · see citing works
Transcription polymerase–catalyzed emergence of novel RNA replicons
Jain, N., Blauch, L. R., Szymański, M. R., Das, R., Tang, S. K. Y., Yin, Y. W., & Fire, A. Z. (2020) · Science · doi:10.1126/science.aay0688 · Cited by 32 · see citing works
Harris, C. J., Molnár, A., Müller, S., & Baulcombe, D. C. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv604 · Cited by 31 · see citing works
Placentino, M., Domingues, A. M. D. J., Schreier, J., Dietz, S., Hellmann, S., de Albuquerque, B. F. M., Butter, F., & Ketting, R. F. (2020) · The EMBO Journal · doi:10.15252/embj.2020105280 · Cited by 28 · see citing works
HDAC1 SUMOylation promotes Argonaute-directed transcriptional silencing in C. elegans
Kim, H., Ding, Y., Zhang, G., Yan, Y., Conte, D., Dong, M., & Mello, C. C. (2021) · eLife · doi:10.7554/elife.63299 · Cited by 27 · see citing works
Suen, K. M., Braukmann, F., Butler, R., Bensaddek, D., Akay, A., Lin, C., Milonaitytė, D., Doshi, N., Sapetschnig, A., Lamond, A. I., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-18089-1 · Cited by 27 · see citing works
Raman, P., Zaghab, S. M., Traver, E. C., & Jose, A. M. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx484 · Cited by 26 · see citing works
Self-citationWan, G., Bajaj, L., Fields, B. D., Dodson, A. E., Pagano, D. J., Fei, Y., & Kennedy, S. G. (2021) · The EMBO Journal · doi:10.15252/embj.2020105612 · Cited by 26 · see citing works
Zhao, C., Cai, S., Shi, R., Li, X., Deng, B., Li, R., Yang, S., Huang, J., Liang, Y., Lu, P., et al. (2024) · Nature Cell Biology · doi:10.1038/s41556-024-01514-8 · Cited by 25 · see citing works
Jose, A. M. (2020) · BioEssays · doi:10.1002/bies.201900254 · Cited by 17 · see citing works
Self-citationHeritable epigenetic changes at single genes: challenges and opportunities in Caenorhabditis elegans
Chey, M. S., & Jose, A. M. (2021) · Trends in Genetics · doi:10.1016/j.tig.2021.08.011 · Cited by 17 · see citing works
Self-citationGaeta, A. L., Nourse, J. B., Willicott, K., McKay, L. E., Keogh, C. M., Peter, K., Russell, S. N., Hamamichi, S., Berkowitz, L. A., Caldwell, K. A., et al. (2022) · PLoS Genetics · doi:10.1371/journal.pgen.1010115 · Cited by 15 · see citing works
Compartmentalized localization of perinuclear proteins within germ granules in C. elegansPreprint
Huang, X., Feng, X., Yan, Y.-H., Xu, D., Wang, K., Zhu, C., Dong, M., Huang, X., Guang, S., & Chen, X. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.03.25.586584 · Cited by 15 · see citing works
Small RNAs couple embryonic developmental programs to gut microbes
Ohno, H., & Bao, Z. (2022) · Science Advances · doi:10.1126/sciadv.abl7663 · Cited by 13 · see citing works
Ravikumar, S., Devanapally, S., & Jose, A. M. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz748 · Cited by 12 · see citing works
Self-citationTissue homogeneity requires inhibition of unequal gene silencing during development
Lê, H. M. N., Looney, M. M., Strauss, B., Bloodgood, M., & Jose, A. M. (2016) · The Journal of Cell Biology · doi:10.1083/jcb.201601050 · Cited by 9 · see citing works
Self-citation
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Intraspecific variation in the duration of epigenetic inheritance in wild isolates of C. elegans
Frejacques, F., Saglio, M., Aljohani, M. D., Chervova, A. A., Bourdon, L., Pelletier, K., Cecere, G., Frøkjær‐Jensen, C., Frézal, L., & Félix, M. (2026) · Current Biology · doi:10.1016/j.cub.2026.02.040 · Cited by 5 · see citing works
Lalit, F., & Jose, A. M. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkae1246 · Cited by 3 · see citing works
Self-citationImplications for OLE RNA as a natural integral membrane RNA
Lyon, S. E., & Breaker, R. R. (2025) · RNA · doi:10.1261/rna.080489.125 · Cited by 3 · see citing works
Beyond Binary Thinking, a Philosophy of Epigenetics and RNA
Rabin, J. S. (2026) · SpringerBriefs in psychology · doi:10.1007/978-3-032-09952-5_7
Two SID-1-dependent genes sensitive to heritable epigenetic changes can also impact reproductionPreprint
Sathya, A., Shugarts, N., Yi, A., & Jose, A. M. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.06.08.730950
Self-citationThe Concept of Gene: History and RNA-Driven Evolution
Haseltine, W. A., & Patarca, R. (2026) · Springer eBooks · doi:10.1007/978-3-032-31089-7_3
- Authors
- Shugarts Devanapally, N. M., Sathya, A., Yi, A. L., Chan, W. M., Marre, J. A., & Jose, A. M.
- Affiliations
- Department of Cell Biology and Molecular Genetics, University of Maryland
- University of Maryland, College Park (US)
- Corresponding author
- Jose, Antony M
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2025-02-04
- Volume
- 13
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC11793870
- OpenAlex
- W4407139509
- Cited by
- 6
- References
- 117
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 1
- Type
- posted content
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute of General Medical Sciences (R01GM111457, R01GM124356)
- University of Maryland (UMD CMNS Dean's Matching Award for "Training Program in Cell and Molecular Biology" T32GM080201)
- National Science Foundation (2120895)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- double-stranded RNA, SID-1, SDG 1, germ granules, retrotransposons, epigenetic inheritance, germline, Caenorhabditis elegans
- MeSH terms
- Animals, Membrane Proteins, RNA, Double-Stranded, Caenorhabditis elegans, Retroelements, Caenorhabditis elegans Proteins, RNA Interference, Epigenesis, Genetic
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