Legume Genomics and Genetics 2025, Vol.16, No.5, 225-233 http://cropscipublisher.com/index.php/lgg 232 process. Not all regulations require alterations to the DNA itself. Some changes-such as DNA methylation, histone modification, and even the involvement of non-coding RNA-can all regulate the expression state without altering the gene sequence. This "soft regulation" approach is sometimes more flexible than the traditional sense of mutation, especially when dealing with changes in the external environment or the switching of developmental nodes. However, it is not easy to clarify how nodules are coordinated by these mechanisms. DNA demethylation mostly occurs in the early stage of infection, especially near key promoters. It's a bit like opening a gate to activate the signal path. Histone modifications, such as activation markers like H3K4me3 or inhibitory markers like H3K27me3, are like tuning buttons that determine which genes are strong and which are weak. Chromatin remodeling complexes, mirnas, lncrnas, etc. are even involved in the fine regulation of transcription factor regulation, further enriching the regulatory hierarchy. These mechanisms are linked together to jointly construct a highly dynamic and malleable epigenetic landscape-its existence is precisely the key to the success or failure of symbiosis. Although we currently know that these mechanisms are roughly at work, many details remain unsolved. For instance, those observed epigenetic markers, are they causes or effects? For instance, at which stage of development is a certain regulatory state established? Or, will it be disrupted due to drought or changes in soil nitrogen concentration? There is no clear answer to this kind of question at present. Furthermore, to what extent do intraspecific and interspecific epigenetic differences affect symbiotic efficiency? Does epigenetic "interaction" exist between the host and rhizobia? These are almost still blank fields. To truly clarify these issues, it may be necessary to rely on the joint efforts of multiple disciplines, integrating experiments and calculations. From an agricultural perspective, these studies are not merely "scientific issues". In the future, without rewriting DNA sequences, there is hope to increase the number, size or nitrogen fixation efficiency of root nodules merely through epigenomic editing. Furthermore, "fingerprints" like epigenetic markers may also provide new tools for the breeding of leguminous crops. Especially in today's context of rising climate uncertainty, understanding how epigenetic plasticity affects the relationship between plants and microorganisms may help us develop more resilient agricultural systems. Acknowledgments We are very grateful to Mr. Tian for reviewing the manuscript and his suggestions improved the interpretation of the conclusion section. Conflict of Interest Disclosure The authors affirm that this research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest. References Baldini A., Battaglia F., and Perrella G., 2025, The generation of novel epialleles in plants: the prospective behind re-shaping the epigenome, Frontiers in Plant Science, 16: 1544744. https://doi.org/10.3389/fpls.2025.1544744 Cheng Y., He C., Wang M., X., Mo F., Yang S., Han J., and Wei X., 2019, Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials, Signal Transduction and Targeted Therapy, 4: 62. https://doi.org/10.1038/s41392-019-0095-0 Davalos V., and Esteller M., 2022, Cancer epigenetics in clinical practice, CA: A Cancer Journal for Clinicians, 73(4): 376-424. https://doi.org/10.3322/caac.21765 Gu M., Ren B., Fang Y., Ren J., Liu X., Wang X., Zhou F., Xiao R., Luo X., You L., and Zhao Y., 2024, Epigenetic regulation in cancer, MedComm, 5(2): e495. https://doi.org/10.1002/mco2.495 Huang W.Z., 2024, Boosting soil health: the role of rhizobium in legume nitrogen fixation, Molecular Soil Biology, 15(3): 129-139. https://doi.org/10.5376/msb.2024.15.0014 Huo M., Zhang J., Huang W., and Wang Y., 2021, Interplay among metabolism, epigenetic modifications, and gene expression in cancer, Frontiers in Cell and Developmental Biology, 9: 793428. https://doi.org/10.3389/fcell.2021.793428
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