Nanoparticle-Delivered siRNA Targeting NSUN4 Relieves Systemic Lupus Erythematosus through Declining Mitophagy-Mediated CD8+T Cell Exhaustion

Abstract

5-Methylcytosine modification (m5C) is an important posttranscriptional regulatory mechanism of gene expression. Exhausted CD8+T cells contribute to the development of many major diseases; however, their exact role and relationship to m5C in systemic lupus erythematosus (SLE) remain unknown. In this study, we identified a CD7^highCD74^high CD8+T subgroup that were robustly expanded in SLE patients through single-cell transcriptome sequencing (scRNA-seq). CD7^highCD74^high CD8+T cells displayed exhausted features and exhibited a superior diagnostic value in SLE. Then, we explored the m5C landscape of SLE patients by performing m5C epitranscriptome sequencing (m5C-seq). ScRNA-seq and m5C-seq were conjointly analyzed to screen m5C-related therapeutic targets for SLE, and NOP2/Sun RNA methyltransferase 4 (NSUN4) was identified as a key regulator of SLE pathogenesis. Knockdown of NSUN4 downregulated CD74 expression via reduction of m5C and suppressed CD8+T cell exhaustion by declining CD44/mTOR (mechanistic target of rapamycin kinase)-mediated mitophagy. Finally, we verified that nanoparticle-delivered siRNA against Nusn4 decreased autoimmune reaction kidney damage in both spontaneous and pristane-induced SLE mouse models. In conclusion, we identify an exhausted CD7^highCD74^high CD8+T cell subset and propose the crucial role of NSUN4/CD74-induced dysregulation of mitophagy in SLE pathogenesis, and targeting NSUN4 is a promising treatment strategy for SLE patients.

Keywords

CD8+T cell mitophagy and exhaustion / nanoparticle-delivered siRNA / NSUN4 / single-cell RNA sequencing and m5C sequencing / systemic lupus erythematosus

References

[1] M. Kiriakidou, C. L. Ching, “Systemic Lupus Erythematosus,” Annals of Internal Medicine 172, no. 11 (2020): 81-96.

[2] D. C. Quintero-González, M. Muñoz-Urbano, G. Vásquez “Mitochondria as a Key Player in Systemic Lupus Erythematosus,” Autoimmunity 55, no. 8 (2022): 497-505.

[3] N. Bolouri, M. Akhtari, E. Farhadi, et al., “Role of the Innate and Adaptive Immune Responses in the Pathogenesis of Systemic Lupus Erythematosus,” Inflammation Research 71, no. 5-6 (2022): 537-554.

[4] P. M. Chen, G. C. Tsokos, “The Role of CD8+ T-Cell Systemic Lupus Erythematosus Pathogenesis: An Update,” Current Opinion in Rheumatology 33, no. 6 (2021): 586-591.

[5] N. Buang, L. Tapeng, V. Gray, et al., “Type I Interferons Affect the Metabolic Fitness of CD8(+) T Cells From Patients With Systemic Lupus Erythematosus,” Nature Communications 12, no. 1 (2021): 1980.

[6] G. Lima, F. Treviño-Tello, Y. Atisha-Fregoso, L. Llorente, H. Fragoso-Loyo, J. Jakez-Ocampo, “Exhausted T Cells in Systemic Lupus Erythematosus Patients in Long-Standing Remission,” Clinical and Experimental Immunology 204, no. 3 (2021): 285-295.

[7] R. K. Perez, M. G. Gordon, M. Subramaniam, et al., “Single-Cell RNA-seq Reveals Cell Type-Specific Molecular and Genetic Associations to Lupus,” Science 376, no. 6589 (2022): eabf1970.

[8] D. Nehar-Belaid, S. Hong, R. Marches, et al., “Mapping Systemic Lupus Erythematosus Heterogeneity at the Single-Cell Level,” Nature Immunology 21, no. 9 (2020): 1094-1106.

[9] M. Zheng, Z. Hu, X. Mei, et al., “Single-Cell Sequencing Shows Cellular Heterogeneity of Cutaneous Lesions in Lupus Erythematosus,” Nature Communications 13, no. 1 (2022): 7489.

[10] C. Guo, Q. Liu, D. Zong, et al., “Single-Cell Transcriptome Profiling and Chromatin Accessibility Reveal an Exhausted Regulatory CD4+ T Cell Subset in Systemic Lupus Erythematosus,” Cell Reports 41, no. 6 (2022): 111606.

[11] L. Cui, R. Ma, J. Cai, et al., “RNA Modifications: Importance in Immune Cell Biology and Related Diseases,” Signal Transduction and Targeted Therapy 7, no. 1 (2022): 334.

[12] E. Sendinc, Y. Shi, “RNA m6A Methylation Across the Transcriptome,” Molecular Cell 83, no. 3 (2023): 428-441.

[13] K. Boulias, E. L. Greer, “Biological Roles of Adenine Methylation in RNA,” Nature Reviews Genetics 24, no. 3 (2023): 143-160.

[14] J. Wu, L. J. Deng, Y. R. Xia, et al., “Involvement of N6-Methyladenosine Modifications of Long Noncoding RNAs in Systemic Lupus Erythematosus,” Molecular Immunology 143 (2022): 77-84.

[15] Q. Luo, J. Rao, L. Zhang, et al., “The Study of METTL14, ALKBH5, and YTHDF2 in Peripheral Blood Mononuclear Cells From Systemic Lupus Erythematosus,” Molecular Genetics & Genomic Medicine 8, no. 9 (2020): e1298.

[16] S. Lu, X. Wei, H. Zhu, et al., “m(6)A Methyltransferase METTL3 Programs CD4(+) T-Cell Activation and Effector T-Cell Differentiation in Systemic Lupus Erythematosus,” Molecular Medicine 29, no. 1 (2023): 46.

[17] L. J. Deng, X. Y. Fang, J. Wu, et al., “ALKBH5 Expression Could Affect the Function of T Cells in Systemic Lupus Erythematosus Patients: A Case-Control Study,” Current Pharmaceutical Design 28, no. 27 (2022): 2270-2278.

[18] Q. Luo, B. Fu, L. Zhang, Y. Guo, Z. Huang, J. Li, “Decreased Peripheral Blood ALKBH5 Correlates With Markers of Autoimmune Response in Systemic Lupus Erythematosus,” Disease Markers 2020 (2020): 8193895.

[19] X. Lv, X. Liu, M. Zhao, et al., “RNA Methylation in Systemic Lupus Erythematosus,” Frontiers in Cell and Developmental Biology 9 (2021): 696559.

[20] L. J. Li, Y. G. Fan, R. X. Leng, H. F. Pan, D. Q. Ye, “Potential Link Between m(6)A Modification and Systemic Lupus Erythematosus,” Molecular Immunology 93 (2018): 55-63.

[21] H. Li, A. Boulougoura, Y. Endo, G. C. Tsokos, “Abnormalities of T Cells in Systemic Lupus Erythematosus: New Insights in Pathogenesis and Therapeutic Strategies,” Journal of Autoimmunity 132 (2022): 102870.

[22] H. Xiong, M. Cui, N. Kong, et al., “Cytotoxic CD161(-)CD8(+) T(EMRA) Cells Contribute to the Pathogenesis of Systemic Lupus Erythematosus,” EBioMedicine 90 (2023): 104507.

[23] D. Denk, V. Petrocelli, C. Conche, et al., “Expansion of T Memory Stem Cells With Superior Anti-Tumor Immunity by Urolithin A-Induced Mitophagy,” Immunity 55, no. 11 (2022): 2059-2073.e2058.

[24] W. Li, H. Cheng, G. Li, L. Zhang, “Mitochondrial Damage and the Road to Exhaustion,” Cell Metabolism 32, no. 6 (2020): 905-907.

[25] L. Chen, Z. Yin, X. Qin, et al., “CD74 Ablation Rescues Type 2 Diabetes Mellitus-Induced Cardiac Remodeling and Contractile Dysfunction Through Pyroptosis-Evoked Regulation of Ferroptosis,” Pharmacological Research 176 (2022): 106086.

[26] R. De, S. Sarkar, S. Mazumder, et al., “Macrophage Migration Inhibitory Factor Regulates Mitochondrial Dynamics and Cell Growth of Human Cancer Cell Lines Through CD74-NF-κB Signaling,” Journal of Biological Chemistry 293, no. 51 (2018): 19740-19760.

[27] H. Fan, F. Liu, G. Dong, et al., “Activation-Induced Necroptosis Contributes to B-Cell Lymphopenia in Active Systemic Lupus Erythematosus,” Cell Death & Disease 5, no. 9 (2014): e1416.

[28] R. Kansal, N. Richardson, I. Neeli, et al., “Sustained B Cell Depletion by CD19-Targeted CAR T Cells Is a Highly Effective Treatment for Murine Lupus,” Science Translational Medicine 11, no. 482 (2019): eaav1648.

[29] K. Ma, W. Du, X. Wang, et al., “Multiple Functions of B Cells in the Pathogenesis of Systemic Lupus Erythematosus,” International Journal of Molecular Sciences 20, no. 23 (2019): 6021.

[30] Q. Pan, Y. Cheng, D. Cheng, “Identification of CD8+ T Cell-Related Genes: Correlations With Immune Phenotypes and Outcomes of Liver Cancer,” Journal of Immunology Research 2021 (2021): 9960905.

[31] C. Guo, Y. Tang, Q. Li, et al., “Deciphering the Immune Heterogeneity Dominated by Natural Killer Cells With Prognostic and Therapeutic Implications in Hepatocellular Carcinoma,” Computers in Biology and Medicine 158 (2023): 106872.

[32] S. S. Ng, F. De Labastida Rivera, J. Yan, et al., “The NK Cell Granule Protein NKG7 Regulates Cytotoxic Granule Exocytosis and Inflammation,” Nature Immunology 21, no. 10 (2020): 1205-1218.

[33] M. Zheng, W. Zhou, C. Huang, et al., “A Single-Cell Map of Peripheral Alterations After FMT Treatment in Patients With Systemic Lupus Erythematosus,” Journal of Autoimmunity 135 (2023): 102989.

[34] X. Y. Li, D. Corvino, B. Nowlan, et al., “NKG7 Is Required for Optimal Antitumor T-Cell Immunity,” Cancer Immunology Research 10, no. 2 (2022): 154-161.

[35] E. J. Lelliott, K. M. Ramsbottom, M. R. Dowling, et al., “NKG7 Enhances CD8+ T Cell Synapse Efficiency to Limit Inflammation,” Frontiers in Immunology 13 (2022): 931630.

[36] T. Wen, W. Barham, Y. Li, et al., “NKG7 Is a T-Cell-Intrinsic Therapeutic Target for Improving Antitumor Cytotoxicity and Cancer Immunotherapy,” Cancer Immunology Research 10, no. 2 (2022): 162-181.

[37] A. Freiwan, J. T. Zoine, J. C. Crawford, et al., “Engineering Naturally Occurring CD7- T Cells for the Immunotherapy of Hematological Malignancies,” Blood 140, no. 25 (2022): 2684-2696.

[38] Y. Hu, Y. Zhou, M. Zhang, et al., “Genetically Modified CD7-Targeting Allogeneic CAR-T Cell Therapy With Enhanced Efficacy for Relapsed/Refractory CD7-Positive Hematological Malignancies: A Phase I Clinical Study,” Cell Research 32, no. 11 (2022): 995-1007.

[39] W. Chen, H. Shi, Z. Liu, et al., “Single-Cell Transcriptomics Reveals Immune Reconstitution in Patients With R/R T-ALL/LBL Treated With Donor-Derived CD7 CAR-T Therapy,” Clinical Cancer Research 29, no. 8 (2023): 1484-1495.

[40] V. Strand, “The Emerging Role of Biologics in Rheumatic Disease,” Journal of Rheumatology Supplement 33 (1992): 40-45.

[41] S. M. Ragab, M. A. Soliman, “P-Glycoprotein-1 Functional Activity in CD5+CD7+ and CD20+ Lymphocytes in Systemic Lupus Erythematosus Children: Relation to Disease Activity, Complications and Steroid Response,” The Egyptian Journal of Immunology 20, no. 2 (2013): 101-115.

[42] L. Valiño-Rivas, C. Baeza-Bermejillo, L. Gonzalez-Lafuente, A. B. Sanz, A. Ortiz, M. D. Sanchez-Niño, “CD74 in Kidney Disease,” Frontiers in Immunology 6 (2015): 483.

[43] L. Qin, J. Tan, X. Lv, J. Zhang, “Vanillic Acid Alleviates Liver Fibrosis Through Inhibiting Autophagy in Hepatic Stellate Cells via the MIF/CD74 Signaling Pathway,” Biomedicine & Pharmacotherapy 168 (2023): 115673.

[44] Q. L. Li, J. Tang, L. Zhao, A. Ruze, X. F. Shan, X. M. Gao, “The Role of CD74 in Cardiovascular Disease,” Frontiers in Cardiovascular Medicine 9 (2022): 1049143.

[45] L. Fernandez-Cuesta, D. Plenker, H. Osada, et al., “CD74-NRG1 Fusions in Lung Adenocarcinoma,” Cancer Discovery 4, no. 4 (2014): 415-422.

[46] N. Xiao, K. Li, X. Zhu, et al., “CD74(+) Macrophages Are Associated With Favorable Prognosis and Immune Contexture in Hepatocellular Carcinoma,” Cancer Immunology, Immunotherapy 71, no. 1 (2022): 57-69.

[47] B. L. Woolbright, G. Rajendran, E. Abbott, et al., “Role of MIF1/MIF2/CD74 Interactions in Bladder Cancer,” Journal of Pathology 259, no. 1 (2023): 46-55.

[48] Z. Xiang, Z. Tian, G. Wang, et al., “CD74 Interacts With Proteins of Enterovirus D68 To Inhibit Virus Replication,” Microbiology Spectrum 11, no. 4 (2023): e0080123.

[49] R. Meza-Romero, G. Benedek, X. Yu, et al., “HLA-DRα1 Constructs Block CD74 Expression and MIF Effects in Experimental Autoimmune Encephalomyelitis,” Journal of Immunology 192, no. 9 (2014): 4164-4173.

[50] M. M. Abdelaziz, R. M. Gamal, N. M. Ismail, R. A. Lafy, H. F. Hetta, “Diagnostic Value of Anti-CD74 Antibodies in Early and Late Axial Spondyloarthritis and Its Relationship to Disease Activity,” Rheumatology 60, no. 1 (2021): 263-268.

[51] D. J. Wallace, F. Figueras, W. A. Wegener, D. M. Goldenberg, “Experience With Milatuzumab, an Anti-CD74 Antibody Against Immunomodulatory Macrophage Migration Inhibitory Factor (MIF) Receptor, for Systemic Lupus Erythematosus (SLE),” Annals of the Rheumatic Diseases 80, no. 7 (2021): 954-955.

[52] J. B. Bilsborrow, E. Doherty, P. V. Tilstam, R. Bucala, “Macrophage Migration Inhibitory Factor (MIF) as a Therapeutic Target for Rheumatoid Arthritis and Systemic Lupus Erythematosus,” Expert Opinion on Therapeutic Targets 23, no. 9 (2019): 733-744.

[53] K. David, G. Friedlander, B. Pellegrino, et al., “CD74 as a Regulator of Transcription in Normal B Cells,” Cell Reports 41, no. 5 (2022): 111572.

[54] L. Przybyl, N. Haase, M. Golic, et al., “CD74-Downregulation of Placental Macrophage-Trophoblastic Interactions in Preeclampsia,” Circulation Research 119, no. 1 (2016): 55-68.

[55] J. Wang, J. Hong, F. Yang, et al., “A Deficient MIF-CD74 Signaling Pathway May Play an Important Role in Immunotherapy-Induced Hyper-Progressive Disease,” Cell Biology and Toxicology 39, no. 3 (2023): 1169-1180.

[56] S. Becker-Herman, M. Rozenberg, C. Hillel-Karniel, “CD74 is a Regulator of Hematopoietic Stem Cell Maintenance,” PLOS Biology 19, no. 3 (2021): e3001121.

[57] J. J. de Winter, M. G. van de Sande, N. Baerlecken, et al., “Anti-CD74 Antibodies Have no Diagnostic Value in Early Axial Spondyloarthritis: Data From the Spondyloarthritis Caught Early (SPACE) Cohort,” Arthritis Research & Therapy 20, no. 1 (2018): 38.

[58] S. Lapter, H. Ben-David, A. Sharabi, et al., “A Role for the B-Cell CD74/Macrophage Migration Inhibitory Factor Pathway in the Immunomodulation of Systemic Lupus Erythematosus by a Therapeutic Tolerogenic Peptide,” Immunology 132, no. 1 (2011): 87-95.

[59] Y. Zhou, H. Chen, L. Liu, et al., “CD74 Deficiency Mitigates Systemic Lupus Erythematosus-Like Autoimmunity and Pathological Findings in Mice,” Journal of Immunology 198, no. 7 (2017): 2568-2577.

[60] Y. R. Yu, H. Imrichova, H. Wang, et al., “Disturbed Mitochondrial Dynamics in CD8(+) TILs Reinforce T Cell Exhaustion,” Nature Immunology 21, no. 12 (2020): 1540-1551.

[61] Y. Tian, H. Guo, X. Miao, et al., “Nestin Protects Podocyte From Injury in Lupus Nephritis by Mitophagy and Oxidative Stress,” Cell Death & Disease 11, no. 5 (2020): 319.

[62] T. N. Caza, D. R. Fernandez, G. Talaber, et al., “HRES-1/Rab4-Mediated Depletion of Drp1 Impairs Mitochondrial Homeostasis and Represents a Target for Treatment in SLE,” Annals of the Rheumatic Diseases 73, no. 10 (2014): 1888-1897.

[63] N. Huang, T. Winans, B. Wyman, et al., “Rab4A-Directed Endosome Traffic Shapes Pro-Inflammatory Mitochondrial Metabolism in T Cells via Mitophagy, CD98 Expression, and Kynurenine-Sensitive mTOR Activation,” Nature Communications 15, no. 1 (2024): 2598.

[64] O. T. Laniak, T. Winans, A. Patel, J. Park, A. Perl, “Redox Pathogenesis in Rheumatic Diseases,” ACR Open Rheumatology 6, no. 6 (2024): 334-346.

[65] P. Gergely, C. Grossman, B. Niland, “Mitochondrial Hyperpolarization and ATP Depletion in Patients With Systemic Lupus Erythematosus,” Arthritis and Rheumatism 46, no. 1 (2002): 175-190.

[66] G. Guo, H. Wang, X. Shi, et al., “Disease Activity-Associated Alteration of mRNA M(5) C Methylation in CD4(+) T Cells of Systemic Lupus Erythematosus,” Frontiers in Cell and Developmental Biology 8 (2020): 430.

[67] K. E. Bohnsack, C. Höbartner, M. T. Bohnsack, “Eukaryotic 5-Methylcytosine (m⁵C) RNA Methyltransferases: Mechanisms, Cellular Functions, and Links to Disease,” Genes (Basel) 10, no. 2 (2019): 102.

[68] M. Li, Z. Tao, Y. Zhao, et al., “5-Methylcytosine RNA Methyltransferases and Their Potential Roles in Cancer,” Journal of Translational Medicine 20, no. 1 (2022): 214.

[69] E. M. Pietras, J. DeGregori, “Dangerous Liaisons Between Tet2 Mutation, Inflammatory Monocytes, and Leukemogenesis,” Cancer Discovery 12, no. 10 (2022): 2234-2236.

[70] E. Solary, O. A. Bernard, A. Tefferi, F. Fuks, W. Vainchenker, “The Ten-Eleven Translocation-2 (TET2) Gene in Hematopoiesis and Hematopoietic Diseases,” Leukemia 28, no. 3 (2014): 485-496.

[71] W. Y. Sung, Y. Z. Lin, D. Y. Hwang, et al., “Methylation of TET2 Promoter Is Associated With Global Hypomethylation and Hypohydroxymethylation in Peripheral Blood Mononuclear Cells of Systemic Lupus Erythematosus Patients,” Diagnostics (Basel) 12, no. 12 (2022): 3006.

[72] H. H. Cheng, L. Hung-Ke, M. L. Sheu, C. Y. Lee, Y. C. Tsai, D. W. Lai, “AHR/TET2/NT5E Axis Downregulation Is Associated With the Risk of Systemic Lupus Erythematosus and Its Progression,” Immunology 168, no. 4 (2023): 654-670.

[73] M. D. Metodiev, H. Spåhr, P. Loguercio Polosa, et al., “NSUN4 is a Dual Function Mitochondrial Protein Required for Both Methylation of 12S rRNA and Coordination of Mitoribosomal Assembly,” PLOS Genetics 10, no. 2 (2014): e1004110.

[74] L. Yang, Z. Ren, S. Yan, et al., “Nsun4 and Mettl3 Mediated Translational Reprogramming of Sox9 Promotes BMSC Chondrogenic Differentiation,” Communications Biology 5, no. 1 (2022): 495.

[75] Y. Wang, Y. Zan, Y. Huang, et al., “NSUN2 Alleviates Doxorubicin-Induced Myocardial Injury Through Nrf2-Mediated Antioxidant Stress,” Cell Death Discovery 9, no. 1 (2023): 43.

[76] C. Ding, J. Lu, J. Li, et al., “RNA-Methyltransferase Nsun5 Controls the Maternal-to-Zygotic Transition by Regulating Maternal mRNA Stability,” Clinical and Translational Medicine 12, no. 12 (2022): e1137.

[77] A. PerezGrovas-Saltijeral, A. P. Rajkumar, H. M. Knight, “Differential Expression of M(5)C RNA Methyltransferase Genes NSUN6 and NSUN7 in Alzheimer's Disease and Traumatic Brain Injury,” Molecular Neurobiology 60, no. 4 (2023): 2223-2235.

[78] S. L. Wolock, R. Lopez, A. M. Klein, “Scrublet: Computational Identification of Cell Doublets in Single-Cell Transcriptomic Data,” Cell Systems 8, no. 4 (2019): 281-291.e289.

[79] Y. Hao, S. Hao, E. Andersen-Nissen, et al., “Integrated Analysis of Multimodal Single-Cell Data,” Cell 184, no. 13 (2021): 3573-3587.

[80] D. Aran, A. P. Looney, L. Liu, et al., “Reference-Based Analysis of Lung Single-Cell Sequencing Reveals a Transitional Profibrotic Macrophage,” Nature Immunology 20, no. 2 (2019): 163-172.

[81] C. Hu, T. Li, Y. Xu, et al., “CellMarker 2.0: An Updated Database of Manually Curated Cell Markers in Human/Mouse and Web Tools Based on scRNA-seq Data,” Nucleic Acids Research 51, no. D1 (2023): D870-D876.

[82] G. Yu, L. G. Wang, Y. Han, Q. Y. He, “clusterProfiler: An R Package for Comparing Biological Themes Among Gene Clusters,” Omics 16, no. 5 (2012): 284-287.

[83] J. Cao, M. Spielmann, X. Qiu, et al., “The Single-Cell Transcriptional Landscape of Mammalian Organogenesis,” Nature 566, no. 7745 (2019): 496-502.

[84] S. Jin, C. F. Guerrero-Juarez, L. Zhang, et al., “Inference and Analysis of Cell-Cell Communication Using CellChat,” Nature Communications 12, no. 1 (2021): 1088.

[85] Z. Gu, R. Eils, M. Schlesner, “Complex Heatmaps Reveal Patterns and Correlations in Multidimensional Genomic Data,” Bioinformatics 32, no. 18 (2016): 2847-2849.

[86] Z. Zhou, M. Zhang, Y. Liu, et al., “Reversible Covalent Cross-Linked Polycations With Enhanced Stability and ATP-Responsive Behavior for Improved siRNA Delivery,” Biomacromolecules 19, no. 9 (2018): 3776-3787.

[87] A. Beauvois, H. Gazon, P. S. Chauhan, et al., “The Helicase-Like Transcription Factor Redirects the Autophagic Flux and Restricts Human T Cell Leukemia Virus Type 1 Infection,” Proceedings of the National Academy of Sciences of the United States of America 120, no. 31 (2023): e2216127120.

[88] B. Liu, A. Li, Y. Qin, et al., “Visualizing Mitophagy With Fluorescent Dyes for Mitochondria and Lysosome,” Journal of Visualized Experiments: JoVE, no. 189 (2022): 192-196.

[89] M. Yazdankhah, S. Ghosh, P. Shang, et al., “BNIP3L-Mediated Mitophagy Is Required for Mitochondrial Remodeling During the Differentiation of Optic Nerve Oligodendrocytes,” Autophagy 17, no. 10 (2021): 3140-3159.

[90] Z. Xu, Y. Wang, L. Zhang, L. Huang, “Nanoparticle-Delivered Transforming Growth Factor-β siRNA Enhances Vaccination Against Advanced Melanoma by Modifying Tumor Microenvironment,” ACS Nano 8, no. 4 (2014): 3636-3645.

[91] D. R. Dou, Y. Zhao, J. A. Belk, et al., “Xist Ribonucleoproteins Promote Female Sex-Biased Autoimmunity,” Cell 187, no. 3 (2024): 733-749.e716.

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