Abstract
Retinoblastoma, the most prevalent primary intraocular tumor in children, leads to vision impairment, disability and even death. In addition to RB1 inactivation, MYCN activation has been documented as another common oncogenic alteration in retinoblastoma and represents one of the high-risk molecular subtypes of retinoblastoma. However, how MYCN contributes to the progression of retinoblastoma is still incompletely understood. Here, we report that MYCN upregulates YTHDF1, which encodes one of the reader proteins for N6-methyladenosine (m6A) RNA modification, in retinoblastoma. We further found that this MYCN-upregulated m6A reader functions to promote retinoblastoma cell proliferation and tumor growth in an m6A binding-dependent manner. Mechanistically, YTHDF1 promotes the expression of multiple oncogenes by binding to their mRNAs and enhancing mRNA stability and translation in retinoblastoma cells. Taken together, our findings reveal a novel MYCN-YTHDF1 regulatory cascade in controlling retinoblastoma cell proliferation and tumor growth, pinpointing an unprecedented mechanism for MYCN amplification and/or activation to promote retinoblastoma progression.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
RNA-seq of retinoblastoma samples, YTHDF1-RIP-seq, MYCN CUT&Tag and m6A-meRIP-seq have been deposited in the National Omics Data Encyclopedia database (NODE, https://www.biosino.org/node/index, Project number: OEP000103 and OEP003732). All relevant data are available from the authors upon request.
References
Ambrosini, G., Pratilas, C.A., Qin, L.X., Tadi, M., Surriga, O., Carvajal, R. D., and Schwartz, G.K. (2012). Identification of unique MEK-dependent genes in GNAQ mutant uveal melanoma involved in cell growth, tumor cell invasion, and MEK resistance. Clin Cancer Res 18, 3552–3561.
An, Y., and Duan, H. (2022). The role of m6A RNA methylation in cancer metabolism. Mol Cancer 21, 14.
Asencio-López, L., Torres-Ojeda, A.A., Isaac-Otero, G., and Leal-Leal, C. A. (2015). Treating retinoblastoma in the first year of life in a national tertiary paediatric hospital in Mexico. Acta Paediatr 104, e384–e387.
Barbieri, I., Tzelepis, K., Pandolfini, L., Shi, J., Millán-Zambrano, G., Robson, S.C., Aspris, D., Migliori, V., Bannister, A.J., Han, N., et al. (2017). Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control. Nature 552, 126–131.
Bawankar, P., Lence, T., Paolantoni, C., Haussmann, I.U., Kazlauskiene, M., Jacob, D., Heidelberger, J.B., Richter, F.M., Nallasivan, M.P., Morin, V., et al. (2021). Hakai is required for stabilization of core components of the m6A mRNA methylation machinery. Nat Commun 12, 3778.
Beltran, H. (2014). The N-myc oncogene: maximizing its targets, regulation, and therapeutic potential. Mol Cancer Res 12, 815–822.
Bokar, J.A., Shambaugh, M.E., Polayes, D., Matera, A.G., and Rottman, F. M. (1997). Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA (N6-adenosine)-methyltransferase. RNA 3, 1233–1247.
Bremner, R., and Zacksenhaus, E. (2010). Cyclins, Cdks, E2f, Skp2, and more at the first international RB Tumor Suppressor Meeting. Cancer Res 70, 6114–6118.
Canturk, S., Qaddoumi, I., Khetan, V., Ma, Z., Furmanchuk, A., Antoneli, C.B.G., Sultan, I., Kebudi, R., Sharma, T., Rodriguez-Galindo, C., et al. (2010). Survival of retinoblastoma in less-developed countries impact of socioeconomic and health-related indicators. Br J Ophthalmol 94, 1432–1436.
Chai, P., Jia, R., Jia, R., Pan, H., Wang, S., Ni, H., Wang, H., Zhou, C., Shi, Y., Ge, S., et al. (2018). Dynamic chromosomal tuning of a novel GAU1 lncing driver at chr12p13.32 accelerates tumorigenesis. Nucleic Acids Res–46, 6041–6056.
Chang, G., Shi, L., Ye, Y., Shi, H., Zeng, L., Tiwary, S., Huse, J.T., Huo, L., Ma, L., Ma, Y., et al. (2020). YTHDF3 induces the translation of m6A-enriched gene transcripts to promote breast cancer brain metastasis. Cancer Cell 38, 857–871.e7.
Chellappan, S.P., Hiebert, S., Mudryj, M., Horowitz, J.M., and Nevins, J.R. (1991). The E2F transcription factor is a cellular target for the RB protein. Cell 65, 1053–1061.
Chen, Y., Miao, L., Lin, H., Zhuo, Z., and He, J. (2022). The role of m6A modification in pediatric cancer. Biochim Biophys Acta 1877, 188691.
Cheng, J., Xu, L., Deng, L., Xue, L., Meng, Q., Wei, F., and Wang, J. (2020). RNA N6-methyladenosine modification is required for miR-98/MYCN axis-mediated inhibition of neuroblastoma progression. Sci Rep 10, 13624.
Currais, A., Prior, M., Dargusch, R., Armando, A., Ehren, J., Schubert, D., Quehenberger, O., and Maher, P. (2014). Modulation of p25 and inflammatory pathways by fisetin maintains cognitive function in Alzheimer’s disease transgenic mice. Aging Cell 13, 379–390.
de Rooij, J.D.E., Masetti, R., van den Heuvel-Eibrink, M.M., Cayuela, J. M., Trka, J., Reinhardt, D., Rasche, M., Sonneveld, E., Alonzo, T.A., Fornerod, M., et al. (2016). Recurrent abnormalities can be used for risk group stratification in pediatric AMKL: a retrospective intergroup study. Blood 127, 3424–3430.
Demelash, A., Rudrabhatla, P., Pant, H.C., Wang, X., Amin, N.D., McWhite, C.D., Naizhen, X., and Linnoila, R.I. (2012). Achaete-scute homologue-1 (ASH1) stimulates migration of lung cancer cells through Cdk5/p35 pathway. Mol Biol Cell 23, 2856–2866.
Dimaras, H., Kimani, K., Dimba, E.A., Gronsdahl, P., White, A., Chan, H. S., and Gallie, B.L. (2012). Retinoblastoma. Lancet 379, 1436–1446.
Dominissini, D., Moshitch-Moshkovitz, S., Schwartz, S., Salmon-Divon, M., Ungar, L., Osenberg, S., Cesarkas, K., Jacob-Hirsch, J., Amariglio, N., Kupiec, M., et al. (2012). Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature 485, 201–206.
Drerup, J.M., Hayashi, K., Cui, H., Mettlach, G.L., Long, M.A., Marvin, M., Sun, X., Goldberg, M.S., Lutter, M., and Bibb, J.A. (2010). Attention-deficit/hyperactivity phenotype in mice lacking the cyclin-dependent kinase 5 cofactor p35. Biol Psychiatry 68, 1163–1171.
Field, M.G., Kuznetsoff, J.N., Zhang, M.G., Dollar, J.J., Durante, M.A., Sayegh, Y., Decatur, C.L., Kurtenbach, S., Pelaez, D., and Harbour, J.W. (2022). RB1 loss triggers dependence on ESRRG in retinoblastoma. Sci Adv 8, eabm8466.
Frau, M., Tomasi, M.L., Simile, M.M., Demartis, M.I., Salis, F., Latte, G., Calvisi, D.F., Seddaiu, M.A., Daino, L., Feo, C.F., et al. (2012). Role of transcriptional and posttranscriptional regulation of methionine adenosyltransferases in liver cancer progression. Hepatology 56, 165–175.
Fu, Y., Dominissini, D., Rechavi, G., and He, C. (2014). Gene expression regulation mediated through reversible m6A RNA methylation. Nat Rev Genet 15, 293–306.
Guan, Q., Lin, H., Miao, L., Guo, H., Chen, Y., Zhuo, Z., and He, J. (2022). Functions, mechanisms, and therapeutic implications of METTL14 in human cancer. J Hematol Oncol 15, 13.
Huang, H., Weng, H., and Chen, J. (2020). m6A modification in coding and non-coding RNAs: roles and therapeutic implications in cancer. Cancer Cell 37, 270–288.
Irwin, M.S., Naranjo, A., Zhang, F.F., Cohn, S.L., London, W.B., Gastier-Foster, J.M., Ramirez, N.C., Pfau, R., Reshmi, S., Wagner, E., et al. (2021). Revised neuroblastoma risk classification system: a report from the Children’s Oncology Group. J Clin Oncol 39, 3229–3241.
Jia, G., Fu, Y., Zhao, X., Dai, Q., Zheng, G., Yang, Y., Yi, C., Lindahl, T., Pan, T., Yang, Y.G., et al. (2011). N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol 7, 885–887.
Jia, R., Chai, P., Wang, S., Sun, B., Xu, Y., Yang, Y., Ge, S., Jia, R., Yang, Y.G., and Fan, X. (2019). m6A modification suppresses ocular melanoma through modulating HINT2 mRNA translation. Mol Cancer 18, 161.
Jung, M.S., Russell, A.J., Liu, B., George, J., Liu, P.Y., Liu, T., DeFazio, A., Bowtell, D.D.L., Oberthuer, A., London, W.B., et al. (2017). A Myc activity signature predicts poor clinical outcomes in Myc-associated cancers. Cancer Res 77, 971–981.
Kalev, P., Hyer, M.L., Gross, S., Konteatis, Z., Chen, C.C., Fletcher, M., Lein, M., Aguado-Fraile, E., Frank, V., Barnett, A., et al. (2021). MAT2A inhibition blocks the growth of MTAP-deleted cancer cells by reducing PRMT5-dependent mRNA splicing and inducing DNA damage. Cancer Cell 39, 209–224.e11.
Ke, S., Alemu, E.A., Mertens, C., Gantman, E.C., Fak, J.J., Mele, A., Haripal, B., Zucker-Scharff, I., Moore, M.J., Park, C.Y., et al. (2015). A majority of m6A residues are in the last exons, allowing the potential for 3′ UTR regulation. Genes Dev 29, 2037–2053.
Kivelä, T. (2009). The epidemiological challenge of the most frequent eye cancer: retinoblastoma, an issue of birth and death. Br J Ophthalmol 93, 1129–1131.
Kooi, I.E., Mol, B.M., Moll, A.C., van der Valk, P., de Jong, M.C., de Graaf, P., van Mil, S.E., Schouten-van Meeteren, A.Y.N., Meijers-Heijboer, H., Kaspers, G.L., et al. (2015). Loss of photoreceptorness and gain of genomic alterations in retinoblastoma reveal tumor progression. Ebiomedicine 2, 660–670.
Li, J., Xie, H., Ying, Y., Chen, H., Yan, H., He, L., Xu, M., Xu, X., Liang, Z., Liu, B., et al. (2020a). YTHDF2 mediates the mRNA degradation of the tumor suppressors to induce AKT phosphorylation in N6-methyladenosine-dependent way in prostate cancer. Mol Cancer 19, 152.
Li, Q., Ni, Y., Zhang, L., Jiang, R., Xu, J., Yang, H., Hu, Y., Qiu, J., Pu, L., Tang, J., et al. (2021a). HIF-1α-induced expression of m6A reader YTHDF1 drives hypoxia-induced autophagy and malignancy of hepatocellular carcinoma by promoting ATG2A and ATG14 translation. Sig Transduct Target Ther 6, 76.
Li, W., Hao, Y., Zhang, X., Xu, S., and Pang, D. (2022). Targeting RNA N6-methyladenosine modification: a precise weapon in overcoming tumor immune escape. Mol Cancer 21, 176.
Li, X., Liang, Q.X., Lin, J.R., Peng, J., Yang, J.H., Yi, C., Yu, Y., Zhang, Q. C., and Zhou, K.R. (2020b). Epitranscriptomic technologies and analyses. Sci China Life Sci 63, 501–515.
Li, Y., Gu, J., Xu, F., Zhu, Q., Chen, Y., Ge, D., and Lu, C. (2021b). Molecular characterization, biological function, tumor microenvironment association and clinical significance of m6A regulators in lung adenocarcinoma. Brief Bioinform 22.
Liao, S., Sun, H., and Xu, C. (2018). YTH domain: a family of N6-methyladenosine (m6A) readers. Genomics Proteomics Bioinf 16, 99–107.
Lin, Z., Niu, Y., Wan, A., Chen, D., Liang, H., Chen, X., Sun, L., Zhan, S., Chen, L., Cheng, C., et al. (2020). RNA m6A methylation regulates sorafenib resistance in liver cancer through FOXO3-mediated autophagy. EMBO J 39, e103181.
Liu, H., Wang, H., Wei, Z., Zhang, S., Hua, G., Zhang, S.W., Zhang, L., Gao, S.J., Meng, J., Chen, X., et al. (2018). MeT-DB V2.0: elucidating context-specific functions of N6-methyl-adenosine methyltranscriptome. Nucleic Acids Res 46, D281–D287.
Liu, H., Zhang, X., Zhao, Z., Zhu, H., Li, D., Yang, Y., Zhao, W., Zhang, F., Wang, Y., Zhu, L., et al. (2022). CNST is characteristic of leukemia stem cells and is associated with poor prognosis in AML. Front Pharmacol 13, 888243.
Liu, J., Ottaviani, D., Sefta, M., Desbrousses, C., Chapeaublanc, E., Aschero, R., Sirab, N., Lubieniecki, F., Lamas, G., Tonon, L., et al. (2021a). A high-risk retinoblastoma subtype with stemness features, dedifferentiated cone states and neuronal/ganglion cell gene expression. Nat Commun 12, 5578.
Liu, T., Wei, Q., Jin, J., Luo, Q., Liu, Y., Yang, Y., Cheng, C., Li, L., Pi, J., Si, Y., et al. (2020). The m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation. Nucleic Acids Res 48, 3816–3831.
Liu, T., Zheng, X., Wang, C., Wang, C., Jiang, S., Li, B., Chen, P., Xu, W., Zheng, H., Yang, R., et al. (2021b). The m6A “reader” YTHDF1 promotes osteogenesis of bone marrow mesenchymal stem cells through translational control of ZNF839. Cell Death Dis 12, 1078.
Luo, Y., Zhou, C., He, F., Fan, J., Wen, X., Ding, Y., Han, Y., Ding, J., Jin, M., Liu, Z., et al. (2022). Contemporary update of retinoblastoma in China: three-decade changes in epidemiology, clinical features, treatments, and outcomes. Am J Ophthalmol 236, 193–203.
Meyer, K.D., Patil, D.P., Zhou, J., Zinoviev, A., Skabkin, M.A., Elemento, O., Pestova, T.V., Qian, S.B., and Jaffrey, S.R. (2015). 5′ UTR m6A promotes cap-independent translation. Cell 163, 999–1010.
Meyer, K.D., Saletore, Y., Zumbo, P., Elemento, O., Mason, C.E., and Jaffrey, S.R. (2012). Comprehensive analysis of mRNA methylation reveals enrichment in 3’ UTRs and near stop codons. Cell 149, 1635–1646.
Oser, M.G., Fonseca, R., Chakraborty, A.A., Brough, R., Spektor, A., Jennings, R.B., Flaifel, A., Novak, J.S., Gulati, A., Buss, E., et al. (2019). Cells lacking the RB1 tumor suppressor gene are hyperdependent on aurora B kinase for survival. Cancer Discov 9, 230–247.
Paris, J., Morgan, M., Campos, J., Spencer, G.J., Shmakova, A., Ivanova, I., Mapperley, C., Lawson, H., Wotherspoon, D.A., Sepulveda, C., et al. (2019). Targeting the RNA m6A reader YTHDF2 selectively compromises cancer stem cells in acute myeloid leukemia. Cell Stem Cell 25, 137–148.e6.
Patil, D.P., Pickering, B.F., and Jaffrey, S.R. (2018). Reading m6A in the transcriptome: m6A-binding proteins. Trends Cell Biol 28, 113–127.
Ping, X.L., Sun, B.F., Wang, L., Xiao, W., Yang, X., Wang, W.J., Adhikari, S., Shi, Y., Lv, Y., Chen, Y.S., et al. (2014). Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res 24, 177–189.
Pozo, K., and Bibb, J.A. (2016). The emerging role of Cdk5 in cancer. Trends Cancer 2, 606–618.
Qin, X.Y., Suzuki, H., Honda, M., Okada, H., Kaneko, S., Inoue, I., Ebisui, E., Hashimoto, K., Carninci, P., Kanki, K., et al. (2018). Prevention of hepatocellular carcinoma by targeting MYCN-positive liver cancer stem cells with acyclic retinoid. Proc Natl Acad Sci USA 115, 4969–4974.
Rushlow, D.E., Mol, B.M., Kennett, J.Y., Yee, S., Pajovic, S., Thériault, B. L., Prigoda-Lee, N.L., Spencer, C., Dimaras, H., Corson, T.W., et al. (2013). Characterisation of retinoblastomas without RB1 mutations: genomic, gene expression, and clinical studies. Lancet Oncol 14, 327–334.
Saw, P.E., Xu, X., Chen, J., and Song, E.W. (2021). Non-coding RNAs: the new central dogma of cancer biology. Sci China Life Sci 64, 22–50.
Schwartz, S., Mumbach, M.R., Jovanovic, M., Wang, T., Maciag, K., Bushkin, G.G., Mertins, P., Ter-Ovanesyan, D., Habib, N., Cacchiarelli, D., et al. (2014). Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5′ sites. Cell Rep 8, 284–296.
Shen, M., Li, Y., Wang, Y., Shao, J., Zhang, F., Yin, G., Chen, A., Zhang, Z., and Zheng, S. (2021). N6-methyladenosine modification regulates ferroptosis through autophagy signaling pathway in hepatic stellate cells. Redox Biol 47, 102151.
Shi, Y., Fan, S., Wu, M., Zuo, Z., Li, X., Jiang, L., Shen, Q., Xu, P., Zeng, L., Zhou, Y., et al. (2019). YTHDF1 links hypoxia adaptation and non-small cell lung cancer progression. Nat Commun 10, 4892.
Strock, C.J., Park, J.I., Nakakura, E.K., Bova, G.S., Isaacs, J.T., Ball, D.W., and Nelkin, B.D. (2006). Cyclin-dependent kinase 5 activity controls cell motility and metastatic potential of prostate cancer cells. Cancer Res 66, 7509–7515.
Wang, S., Gao, S., Zeng, Y., Zhu, L., Mo, Y., Wong, C.C., Bao, Y., Su, P., Zhai, J., Wang, L., et al. (2022). N6-methyladenosine reader YTHDF1 promotes ARHGEF2 translation and RhoA signaling in colorectal cancer. Gastroenterology 162, 1183–1196.
Wang, T., Kong, S., Tao, M., and Ju, S. (2020a). The potential role of RNA N6-methyladenosine in cancer progression. Mol Cancer 19, 88.
Wang, X., Lu, Z., Gomez, A., Hon, G.C., Yue, Y., Han, D., Fu, Y., Parisien, M., Dai, Q., Jia, G., et al. (2014). N6-methyladenosine-dependent regulation of messenger RNA stability. Nature 505, 117–120.
Wang, X., Zhao, B.S., Roundtree, I.A., Lu, Z., Han, D., Ma, H., Weng, X., Chen, K., Shi, H., and He, C. (2015). N6-methyladenosine modulates messenger RNA translation efficiency. Cell 161, 1388–1399.
Wang, Y., Bao, Y., Zhang, S., and Wang, Z. (2020b). Splicing dysregulation in cancer: from mechanistic understanding to a new class of therapeutic targets. Sci China Life Sci 63, 469–484.
Xiong, J., He, J., Zhu, J., Pan, J., Liao, W., Ye, H., Wang, H., Song, Y., Du, Y., Cui, B., et al. (2022). Lactylation-driven METTL3-mediated RNA m6A modification promotes immunosuppression of tumor-infiltrating myeloid cells. Mol Cell 82, 1660–1677.e10.
Xu, C., Liu, K., Ahmed, H., Loppnau, P., Schapira, M., and Min, J. (2015). Structural basis for the discriminative recognition of N6-methyladenosine RNA by the human YT521-B homology domain family of proteins. J Biol Chem 290, 24902–24913.
Xu, Y., He, X., Wang, S., Sun, B., Jia, R., Chai, P., Li, F., Yang, Y., Ge, S., Jia, R., et al. (2022). The m6A reading protein YTHDF3 potentiates tumorigenicity of cancer stem-like cells in ocular melanoma through facilitating CTNNB1 translation. Oncogene 41, 1281–1297.
Xue, Y., Chen, R., Qu, L., and Cao, X. (2020). Noncoding RNA: from dark matter to bright star. Sci China Life Sci 63, 463–468.
Yin, H., Zhang, X., Yang, P., Zhang, X., Peng, Y., Li, D., Yu, Y., Wu, Y., Wang, Y., Zhang, J., et al. (2021). RNA m6A methylation orchestrates cancer growth and metastasis via macrophage reprogramming. Nat Commun 12, 1394.
Yu, J., Chai, P., Xie, M., Ge, S., Ruan, J., Fan, X., and Jia, R. (2021). Histone lactylation drives oncogenesis by facilitating m6A reader protein YTHDF2 expression in ocular melanoma. Genome Biol 22, 85.
Yue, Y., Liu, J., and He, C. (2015). RNA N6-methyladenosine methylation in post-transcriptional gene expression regulation. Genes Dev 29, 1343–1355.
Zeng, Z., Cao, Z., Zhang, E., Huang, H., and Tang, Y. (2021). Elevated CDK5R1 predicts worse prognosis in hepatocellular carcinoma based on TCGA data. Biosci Rep 41.
Zhang, C., and Zhang, B. (2023). RNA therapeutics: updates and future potential. Sci China Life Sci 66, 12–30.
Zhang, J., Benavente, C.A., McEvoy, J., Flores-Otero, J., Ding, L., Chen, X., Ulyanov, A., Wu, G., Wilson, M., Wang, J., et al. (2012). A novel retinoblastoma therapy from genomic and epigenetic analyses. Nature 481, 329–334.
Zheng, G., Dahl, J.A., Niu, Y., Fedorcsak, P., Huang, C.M., Li, C.J., Vågbø, C.B., Shi, Y., Wang, W.L., Song, S.H., et al. (2013). ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell 49, 18–29.
Zhong, L., Liao, D., Zhang, M., Zeng, C., Li, X., Zhang, R., Ma, H., and Kang, T. (2019). YTHDF2 suppresses cell proliferation and growth via destabilizing the EGFR mRNA in hepatocellular carcinoma. Cancer Lett 442, 252–261.
Zhou, J., Wan, J., Gao, X., Zhang, X., Jaffrey, S.R., and Qian, S.B. (2015). Dynamic m6A mRNA methylation directs translational control of heat shock response. Nature 526, 591–594.
Zhou, R., Ni, W., Qin, C., Zhou, Y., Li, Y., Huo, J., Bian, L., Zhou, A., and Li, J. (2022). A functional loop between YTH domain family protein YTHDF3 mediated m6A modification and phosphofructokinase PFKL in glycolysis of hepatocellular carcinoma. J Exp Clin Cancer Res 41, 334.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (81570884, 81872339, and 82272642), Shanghai Municipal Science and Technology Major Project (17JC1420100 and 19JC1410202), Shanghai Science and Technology Development Funds (17DZ2260100 and 19QA1405100) and Ninth People’s Hospital Excellent Youth Fund Program (JYYQ003). We thank members of the Jia’s and Fan’s labs for helpful comments.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Compliance and ethics The author(s) declare that they have no conflict of interest.
Supplemental Data for
11427_2022_2288_MOESM1_ESM.docx
A novel MYCN-YTHDF1 cascade contributes to retinoblastoma tumor growth by eliciting m6A -dependent activation of multiple oncogenes
Rights and permissions
About this article
Cite this article
Luo, Y., He, M., Yang, J. et al. A novel MYCN-YTHDF1 cascade contributes to retinoblastoma tumor growth by eliciting m6A -dependent activation of multiple oncogenes. Sci. China Life Sci. 66, 2138–2151 (2023). https://doi.org/10.1007/s11427-022-2288-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11427-022-2288-4