Dr. Zusen Fan, Professor, Mentor for Ph.D candidates. Deputy Director of the Teaching and Research Department for Infection and Immunity at CAS University, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, CAS. Dr. Fan obtained Ph.D degree in the Medical School of Shanghai Jiaotong University in 1998, and then got postdoctoral training in Harvard Medical School, and promoted Instructor of Harvard University in 2003. Eventually he was recruited to the Institute of Biophysics of CAS as professor in 2004. In 2005, he got the National Outstanding Youth Grant from NSFC. In 2006, he was granted as the National Talents of “Hundred-Thousand-Tenthousand Program”. In 2010, he was awarded as the State Council Expert for Special Allowance. In 2014, he was granted with Tan Jiazhen Life Sciences Innovation Award. In 2014, he was selected as Outstanding Professor of the CAS University. In 2015, he was recruited to the CAS Center for Excellence in Biomacromolecules. In 2016 and 2018, he was awarded to CAS Outstanding Graduate Tutor Award. In 2018, he was awarded as the First prize of Beijing Science and technology progress award. In 2019, he was granted as a principal scientist of Innovation Group Grant of NSFC. In 2020, he was granted as a principal scientist of the National Key R&D Program of China. Fan Lab focuses on these three major research fields: 1) New immune cell subsets and immune mechanisms against infections and tumors; 2) Noncoding RNAs and immune regulations; 3) Mechanisms of reprogramming and self-renewal of cancer stem cells as well as tumor immunotherapy.

1. Identification of new innate immune cell subsets, definition of their effector functions against infections and their mechanisms of trans-differentiation in intestinal diseases

Innate lymphoid cells (ILCs) are located in mucosal surfaces to potentiate immune responses, sustain mucosal integrity and promote lymphoid organogenesis. Group 1 (ILC1) cells are characterized by their capacity to secrete interferon γ (IFN-γ) responding to interleukin 12 (IL-12), IL-15 and IL-18. Group 2 (ILC2) cells generate type 2 T helper (Th2) cell cytokines such as IL-5, IL-9 and IL-13 in response to IL-25 and IL-33 stimulation. Group 3 (ILC3) cells produce IFN-γ, IL-17 and IL-22 upon stimulation with IL-1 and IL-23. However, it is still unclear how ILCs are regulated and how ILCs are transdifferentiated in physiological and pathological settings. We want to identify new subsets of innate immune cells and define their effector functions against infections. We will reveal whether and how ILCs undergo transdifferentiation in physiological and pathological settings and elucidate their underlying mechanisms of transdifferentiation.

2. Discovery of new ncRNAs in innate immune cell subsets and definition of their regulatory roles in immune responses

Long noncoding RNAs (lncRNAs) are defined as transcripts longer than 200 nucleotides (nt) with limited coding potential. LncRNAs function in a wide range of biological processes and can regulate gene expression in cis or in trans by diverse mechanisms. LncRNA-mediated biology has been implicated in many cellular processes. However, how lncRNAs regulate immune cell development and immune responses still remains elusive. We will identify new lncRNAs in ILC lineages and reveal their roles in their development and effector functions in immune responses.

3. Elucidation of reprogramming and self-renewal of cancer stem cells and strategies for tumor immunology

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, ranking the third leading cause of cancer-related deaths. The high rate of recurrence and heterogeneity are the 2 major features of HCC. The cancer stem cell model (CSC model) proposes that only a rare subset of cancer cells within tumor bulk display the capacity to self-renew, differentiate, and generate a new tumor. These CSCs are responsible for sustaining tumor growth and are resistant to conventional treatments, accounting for a hierarchical organization of heterogeneous cancer cells and a high rate of cancerous recurrence. However, the hepatic CSC biology remains largely unknown. We already identified a bunch of important genes and lncRNAs that are implicated in the regulation of liver CSCs. We next sought to elucidate their roles of our identified genes and lncRNA in the self-renewal maintenance of liver CSCs. Finally, we will develop new strategies to block the self-renewal capacity of liver CSCs, leading to new therapy for cancer patients.

2022

1. Z. Xiong, X. Zhu, J. Geng, Y. Xu, R. Wu, C. Li, D. Fan, X. Qin, Y. Du, Y. Tian*, Fan Z*. Intestinal Tuft-2 cells exert antimicrobial immunity via sensing bacterial metabolite N-undecanoylglycine. Immunity. 2022 Apr 12;55(4):686-700

2. P. Zhu, T. Lu, Z. Chen, B. Liu, D. Fan, C. Li, J Wu, L He, X Zhu, Y. Du, Y. Tian, Fan Z*. 5-hydroxytryptamine produced by enteric serotonergic neurons initiates colorectal cancer stem cell self-renewal. Neuron. 2022 7;S0896-6273.

3. P. Zhu, T. Lu, J. Wu, D. Fan, B. Liu, X. Zhu, H. Guo, Y. Du, F. Liu, Y. Tian, Fan Z*. Gut microbiota drives macrophage-dependent self-renewal of intestinal stem cells via niche enteric serotonergic neurons. Cell Res. 32(6),555-569 (2022)

4. N. Liu, J. He, D. Fan, Y. Gu, J. Wang, H. Li, X. Zhu, Y. Du, Y. Tian, B. Liu, Fan Z*. Circular RNA circTmem241 drives group III innate lymphoid cell differentiation via initiation of Elk3 transcription. Nat Commun. 2022 Aug 11;13(1):4711.

5. B. Ye, L. Yang, B. Liu, N. Liu, D. Fan, H. Li, L. Sun, Y. Du, S. Wang, Y. Tian, Fan Z*. Induction of functional neutrophils from mouse fibroblasts by thymidine through enhancement of Tet3 activity. Cell Mol Immunol. 2022 May;19(5):619-633.

6. Hui Guo, Jiahang Zhang, Zhimin Jiang, Xiaoxiao Zhu, Jing Yang, Rui Mu，Ying Du, Yong Tian* Pingping Zhu* & Zusen Fan*. CircBtnl1 suppresses self-renewal of intestinal stem cells via disruption of Atf4 mRNA stability. EMBO J. 2022 Accepted

2021

7. Gu Y, Wang Y, He L, Zhang J, Zhu X, Liu N, Wang J, Lu T, He L, Tian Y*, Fan Z*. Circular RNA circIPO11 drives self-renewal of liver cancer initiating cells via Hedgehog signalling. Mol Cancer. 2021 Oct 14;20(1):132.

8. Wang Y, Wang J, Li X, Xiong X, Wang J, Zhou Z, Zhu X, Dominissini D, Gu Y, He L, Tian Y*, Yi C*, Fan Z*. N 1-methyladenosine methylation in tRNA drives liver tumourigenesis by regulating cholesterol metabolism. Nat Commun. 2021;12(1):6314.

9. Chen Z, Lu T, Huang L, Wang Z, Yan Z, Guan Y, Hu W, Fan Z*, Zhu P*. circular RNA cia-MAF drives self-renewal and metastasis of liver tumor-initiating cells via transcription factor MAFF. J Clin Invest. 2021;148020.

10. Liu B, Liu N, Zhu X, Yang L, Ye B, Li H, Zhu P, Lu T, Tian Y*, Fan Z*. Circular RNA circZbtb20 maintains ILC3 homeostasis and function via Alkbh5-dependent m6A demethylation of Nr4a1 mRNA. Cell Mol Immunol. 2021;18(6):1412-1424.

11. Chen Z, Wu J, Liu B, Zhang G, Wang Z, Zhang L, Wang K, Fan Z*, Zhu P*. Identification of cis-HOX-HOXC10 axis as a therapeutic target for colorectal tumor-initiating cells without APC mutations. Cell Rep. 2021;36(4):109431.

2020

12. Wang S, Qu Y, Xia P, Chen Y, Zhu X, Zhang J, Wang G, Tian Y, Ying J, Fan Z*. Transdifferentiation of tumor infiltrating innate lymphoid cells during progression of colorectal cancer. Cell Res. 2020 Jul;30(7):610-622.

13. Xiong Z, Xia P, Zhu X, Geng J, Wang S, Ye B, Qin X, Qu Y, He L, Fan D, Du Y, Tian Y, Fan Z*. Glutamylation of deubiquitinase BAP1 controls self-renewal of hematopoietic stem cells and hematopoiesis. J Exp Med. 2020 Feb 3;217(2):e20190974

14. Liu B, Ye B, Zhu X, Yang L, Li H, Liu N, Zhu P, Lu T, He L, Tian Y, Fan Z*. An inducible circular RNA circKcnt2 inhibits ILC3 activation to facilitate colitis resolution. Nat Commun. 2020 Aug 14;11(1):4076.

15. Ye B, Yang L, Qian G, Liu B, Zhu X, Zhu P, Ma J, Xie W, Li H, Lu T, Wang Y, Wang S, Du Y, Wang Z, Jiang J, Li J, Fan D, Meng S, Wu J, Tian Y, Fan Z*. The chromatin remodeler SRCAP promotes self-renewal of intestinal stem cells. EMBO J. 2020 Jul 1;39(13):e103786. Epub 2020 May 25.

2019

16. Zhu P, Zhu X, Wu J, He L, Lu T, Wang Y, Liu B, Ye B, Sun L, Fan D, Wang J, Yang L, Qin X, Du Y, Li C, He L, Ren W, Wu X, Tian Y*, Fan Z*. IL-13 secreted by ILC2s promotes the self-renewal of intestinal stem cells through circular RNA circPan3. Nat Immunol. 2019;20(2):183-194.

17. Wu J, Zhu P, Lu T, Du Y, Wang Y, He L, Ye B, Liu B, Yang L, Wang J, Gu Y, Lan J, Hao Y, He L, Fan Z*. The long noncoding RNA LncHDAC2 drives the self-renewal of liver cancer stem cells via activation of Hedgehog Signaling. J Hepatol. 2019;70(5):918-929.

18. Liu B, Yang L, Zhu X, Li H, Zhu P, Wu J, Lu T, He L, Liu N, Meng S, Zhou L, Ye B*, Tian Y*, Fan Z*. Yeats4 drives ILC lineage commitment via activation of Lmo4 transcription. J Exp Med. 2019; pii: jem.20182363.

19. Zhen Xiong^1,2,4, Pengyan Xia^1,4, Xiaoxiao Zhu^3,4, Jingjing Geng^1,2, Shuo Wang¹, Buqing Ye¹, Xiwen Qin^1,2, Yuan Qu^1,2, Luyun He^1,2, Dongdong Fan³, Ying Du¹, Yong Tian^2,3*, Zusen Fan^1,2*. Glutamylation of deubiquitinase BAP1 controls self-renewal of hematopoietic stem cells and hematopoiesis. J Exp Med. 2019 (in press).

20. Wang Y, Zhu P, Luo J, Wang J, Liu Z, Wu W, Du Y, Ye B, Wang D, He L, Ren W, Wang J, Sun X, Chen R, Tian Y*, Fan Z*. LncRNA HAND2-AS1 promotes liver cancer stem cell self-renewal via BMP signaling. EMBO J. 2019 Sep 2;38(17):e101110.

2018

21. Xia P, Wang S, Xiong Z, Zhu X, Ye B, Du Y, Meng S, Qu Y, Liu J, Gao G, Tian Y*, Fan Z*. The ER membrane adaptor ERAdP senses the bacterial second messenger c-di-AMP and initiates anti-bacterial immunity. Nat Immunol. 2018;19(2):141-150.

22. Xia P, Wang S, Ye B, Du Y, Li C, Xiong Z, Qu Y, Fan Z*. A Circular RNA Protects Dormant Hematopoietic Stem Cells from DNA Sensor cGAS-Mediated Exhaustion. Immunity 2018; 48(4):688-701.

23. Zhu P, Wu J, Wang Y, Zhu X, Lu T, Liu B, He L, Ye B, Wang S, Meng S, Fan D, Wang J, Yang L, Qin X, Du Y, Li C, He L, Ren W, Wu X, Tian Y*, Fan Z*. LncGata6 maintains stemness of intestinal stem cells and promotes intestinal tumorigenesis.Nat Cell Biol. 2018; 20(10):1134-1144.

24. Wang Y, Zhu P, Wang J, Zhu X, Luo J, Meng S, Wu J, Ye B, He L, Du Y, He L, Chen R*, TTian Y*, Fan Z*. Long noncoding RNA lncHand2 promotes liver repopulation via c-Met signaling.J Hepatol  2018; 69(4):861-872.

25. Ye B, Liu B, Hao L, Zhu X, Yang L, Wang S, Xia P, Du Y, Meng S, Huang G, Qin X, Wang Y, Yan X, Li C, Hao J, Zhu P, He L, Tian Y*, Fan Z*. Klf4 glutamylation is required for cell reprogramming and early embryonic development in mice.Nat Commun. 2018; 9(1):1261.

26. Ye B, Liu B, Yang L, Zhu X, Zhang D, Wu W, Zhu P, Wang Y, Wang S, Xia P, Du Y, Meng S, Huang G, Wu J, Chen R*, Tian Y*, Fan Z*. LncKdm2b controlsself-renewal of embryonic stem cells viaactivation of transcription factor Zbtb3. EMBO J. 2018; 37(8).

2017

27. Wang S*, Xia P, Chen Y, Qu Y, Xiong Z, Ye B, Du Y, Tian Y, Yin Z, Xu Z, Fan Z*. Regulatory Innate Lymphoid Cells Control Innate Intestinal Inflammation. Cell. 2017;171(1):201-216.

28. Liu B, Ye B, Yang L, Zhu X, Huang G, Zhu P, Du Y, Wu J, Qin X, Chen R*, Tian Y*, Fan Z*. Long non-coding RNA lncKdm2b is required for the maintenance of group 3 innate lymphoid cells by initiating Zfp292 expression. Nat Immunol. 2017;18(5):499-508.

29. Wang S*, Xia P, Fan Z*. Natural-Killer-like B Cells Function as a Separate Subset of Innate B Cells. Immunity. 2017; 47(2):201-202.

30. Xia P, Liu J, Wang S, Ye B, Du Y, Xiong Z, Han ZG, Tong L, Fan Z*. WASH maintains NKp46+ ILC3 cells by promoting AHR expression. Nat Commun. 2017;8:15685.

31. Liu B, Ye B, Zhu X, Huang G, Yang L, Zhu P, Du Y, Wu J, Meng S, Tian Y*, Fan Z*. IL-7Rα glutamylation and activation of transcription factor Sall3 promote group 3 ILC development. Nat Commun. 2017;8(1):231.

32. Ye B, Liu B, Yang L, Huang G, Hao L, Xia P, Wang S, Du Y, Qin X, Zhu P, Wu J, Sakaguchi N, Zhang J, Fan Z*. Suppression of SRCAP chromatin remodelling complex and restriction of lymphoid lineage commitment by Pcid2. Nat Commun. 2017; 8(1): 1518.

33. Yang Z^#, Li C^#, Fan Z^#, Liu H, Zhang X, Cai Z, Xu L, Luo J, Huang Y, He L, Liu C, Wu S. Single-cell Sequencing Reveals Variants in ARID1A, GPRC5A and MLL2 Driving Self-renewal of Human Bladder Cancer Stem Cells. Eur Urol. 2017;71(1):8-12.

34. Yan X, Zhang D, Wu W, Wu S, Qian J, Hao Y, Yan F, Zhu P, Wu J, Huang G, Huang Y, Luo J, Liu X, Liu B, Chen X, Du Y, Chen R*, Fan Z*. Mesenchymal stem cells promote hepatocarcinogenesis via lncRNA-MUF interaction with ANXA2 and miR-34a. Cancer Res. 2017; 77(23):6704-6716.

2016

35. Xia P, Ye B, Wang S, Zhu X, Du Y, Xiong Z, Tian Y*, Fan Z*. Glutamylation of the DNA sensor cGAS regulates its binding and synthase activity in antiviral immunity. Nat Immunol. 2016;17(4):369-78.

36. Wang S, Xia P, Chen Y, Huang G, Xiong Z, Liu J, Li C, Ye B, Du Y, Fan Z*. Natural Killer-like B Cells Prime Innate Lymphocytes against Microbial Infection. Immunity. 2016;45(1):131-44.

37. Zhu P, Wang Y, Huang G, Ye B, Liu B, Wu J, Du Y, He L, Fan Z*. lnc-β-Catm elicits EZH2-dependent β-catenin stabilization and sustains liver CSC self-renewal. Nat Struct Mol Biol. 2016;23(7):631-9.

38. Wang S, Xia P, Huang G, Zhu P, Liu J, Ye B, Du Y, Fan Z*. FoxO1-mediated autophagy is required for NK cell development and innate immunity. Nat Commun. 2016; 7:11023.

39. Zhu P, Wang Y, Wu J, Huang G, Liu B, Ye B, Du Y, Gao G, Tian Y, He L, Fan Z*. LncBRM initiates YAP1 signalling activation to drive self-renewal of liver cancer stem cells. Nat Commun. 2016;7:13608.

40. Li C, Du Y, Yang Z, He L, Wang Y, Hao L, Ding M, Yan R, Wang J*, Fan Z*. GALNT1-Mediated Glycosylation and Activation of Sonic Hedgehog Signaling Maintains the Self-Renewal and Tumor-Initiating Capacity of Bladder Cancer Stem Cells. Cancer Res. 2016;76(5):1273-83.

2015

41. Xia P, Wang S, Ye B, Du Y, Huang G, Zhu P, Fan Z*. Sox2 functions as a sequence-specific DNA sensor in neutrophils to initiate innate immunity against microbial infection. Nat Immunol. 2015; 16(4):366-375.

42. Wang Y, He L, Du Y, Zhu P, Huang G, Luo J, Yan X, Ye B, Li C, Xia P, Zhang G, Tian Y, Chen R*, Fan Z*. The long noncoding RNA lncTCF7 promotes self-renewal of human liver cancer stem cells through activation of Wnt signaling. Cell Stem Cell. 2015; 16(4):413-25.

43. Zhu P, Wang Y, He L, Huang G, Du Y, Zhang G, Yan X, Xia P, Ye B, Wang S, Hao L, Wu J, Fan Z*. ZIC2-dependent OCT4 activation drives self-renewal of human liver cancer stem cells. J Clin Invest. 2015;125(10):3795-808.

44. Xia P, Wang S, Du Y, Huang G, Satoh T, Akira S, Fan Z*. Insulin-InsR signaling drives multipotent progenitor differentiation toward lymphoid lineages. J Exp Med. 2015; 212(13):2305-21.

45. Xia P, Wang S, Xiong Z, Ye B, Huang L, Han Z*, Fan Z*. IRTKS negatively regulates antiviral immunity through PCBP2 sumoylation-mediated MAVS degradation. Nat Commun. 2015;6:8132.

46. Zhu P, Wang Y, Du Y, He L, Huang G, Zhang G, Yan X, Fan Z*. C8orf4 negatively regulates self-renewal of liver cancer stem cells via suppression of NOTCH2 signaling. Nat Commun. 2015; 6:7122.

2014

47. Xia P, Wang S, Huang G, Zhu P, Li M, Ye B, Du Y, Fan Z*. WASH is required for the differentiation commitment of hematopoietic stem cells in a c-Myc-dependent manner. J Exp Med. 2014;211(10): 2119-2134.

48. Ye B, Li C, Yang Z, Wang Y, Hao J, Wang L, Li Y, Du Y, Hao L, Liu B, Wang S, Xia P, Huang G, Sun L, Tian Y*, Fan Z*. Cytosolic carboxypeptidase CCP6 is required for megakaryopoiesis by modulating Mad2 polyglutamylation. J Exp Med. 2014;211(12):2439-2454.

49. Xia P, Wang S, Huang G, Du Y, Zhu P, Li M, Fan Z*. RNF2 is recruited by WASH to ubiquitinate AMBRA1 leading to downregulation of autophagy. Cell Res., 2014; 24:943–958.

50. Li C, Yang Z, Du Y, Tang H, Chen J, Hu D, Fan Z. BCMab1, A Monoclonal Antibody against Aberrantly Glycosylated Integrin α3β1, Has Potent Antitumor Activity of Bladder Cancer In Vivo. Clin Cancer Res. 2014;20(15):4001-13.

51. Ye B, Dai Z, Liu B, Wang R, Li C, Huang G, Wang S, Xia P, Yang X, Kuwahara K, Sakaguchi N, Fan Z. Pcid2 inactivates developmental genes in human and mouse embryonic stem cells to sustain their pluripotency by modulation of Eid1 stability. Stem Cells. 2014;32(3): 623-635.

2013

52. Wang S, Xia P, Ye B, Huang G, Liu J, Fan Z*. Transient activation of autophagy via Sox2-Mediated suppression of mTOR is an important early step in reprogramming to pluripotency. Cell Stem Cell. 2013;13(5):617–625.

53. Xia P, Wang S, Du Y, Zhao Z, Shi L, Sun L, Huang G, Ye B, Li C, Dai Z, Hou N, Cheng X, Sun Q, Li L, Yang X, Fan Z*. WASH inhibits autophagy through suppression of Beclin 1 ubiquitination. EMBO J. 2013;32(20): 2685-2696.

54. Liu S, Zhang H, Li M, Hu D, Li C, Ge B, Jin B, Fan Z*. Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT suppresses granule polarization and cytotoxicity of NK cells. Cell Death Differ. 2013;20(3):456-464.

2012

55. Wang S, Xia P, Shi L, Fan Z*. FADD cleavage by NK cell granzyme M enhances its self-association to facilitate procaspase-8 recruitment for auto-processing leading to caspase cascade. Cell Death Differ. 2012;19(4):605-615. (IF:8.8)

56. Zhong C, Li C, Wang X, Toyoda T, Gao G, Fan Z*. Granzyme K inhibits replication of influenza virus through cleaving the nuclear transport complex importin α1/β dimer of infected host cells. Cell Death Differ. 2012;19(5):882-890.

2011年以前文章

57. Shi L, Wu L, Wang S, Fan Z*. Granzyme F induces a novel death pathway characterized by Bid-independent cytochrome c release without caspase activation. Cell Death Differ. 2009, 16(12): 1694-1706.

58. Zhao T, Zhang H, Guo Y, Zhang Q, Hua G, Lu H, Hou Q, Liu H, Fan Z*. Granzyme K cleaves the nucleosome assembly protein SET to induce single-stranded DNA nicks of target cells. Cell Death Differ. 2007,14(3): 489-499.

59. Fan Z*, Yu P, Wang Y, Wang Y, Fu ML, Liu W, Sun Y, Fu YX*. NK-cell activation by LIGHT triggers tumor-specific CD8+ T-cell immunity to reject established tumors. Blood. 2006, 107(4): 1342-1351.

60. Fan Z*, Zhang H, Zhang Q. Tumor suppressor pp32 represses cell growth through inhibition of transcription by blocking acetylation and phosphorylation of histone H3 and initiating its proapoptotic activity. Cell Death Differ. 2006, 13(9): 1485-1494.

61. Fan Z, Beresford PJ, Oh DY, Zhang D, Lieberman J*. Tumor suppressor NM23-H1 is a granzyme A-activated DNase during CTL-mediated apoptosis, and the nucleosome assembly protein SET is its inhibitor. Cell 2003, 112(5): 659-672.

62. Fan Z, Beresford PJ, Zhang D, Xu Z, Novina CD, Yoshida A, Pommier Y, Lieberman J*. Cleaving the oxidative repair protein Ape1 enhances cell death mediated by granzyme A. Nat Immunol. 2003, 4(2): 145-153.

63. Lieberman J*, Fan Z*. Nuclear war: the granzyme A-bomb. Curr Opin Immunol. 2003, 15(5): 553-559.

64. Fan Z, Beresford PJ, Zhang D, Lieberman J*. HMG2 interacts with the nucleosome assembly protein SET and is a target of the cytotoxic T-lymphocyte protease granzyme A. Mol Cell Biol. 2002, 22(8): 2810-2820.

(From Zusen Fan, January 11, 2023)