目前已知RNA上含有100余种化学修饰，其中m6A, m1A, m5C, pseudouridine, APA是RNA上最主要的几种化学修饰。课题组团队在m6A领域已经做出了系列原创性研究，积累了扎实的学术基础和构建了坚实的实验平台。目前m6A的研究已经成为了一个热点领域，但是大家对于其它类型的RNA修饰关注不是很多，特别是不同的RNA修饰之间如何协调应对外界不同类型的刺激从而协同调控RNA的水平和功能鲜有研究。免疫细胞以及相应的生理病理条件下的免疫反应为研究这一重大前沿问题提供了一个非常好的模型和角度。我们目前的初步研究成果表明各种不同的RNA修饰在T细胞激活的过程中发挥着关键的主动的动态作用，而且这些修饰之间存在着功能上的相互作用和协调。

在接下来的研究中将在以下几个方面开展工作：

（1） m1A RNA 表观遗传修饰在免疫细胞中的功能以及分子机制；

（2） pseudoUridine在免疫细胞中的功能以及其作用的分子机制；

（3） APA在免疫细胞中的功能以及其作用的分子机制；

（4） 开发这些RNA修饰的干预策略应用于肿瘤和炎症的临床前免疫治疗；

（5）不同RNA修饰类型之间的协同作用及其规律。

There are more than 100 types of different chemical RNA modification, among which m6A, m1A, m5C, pseudoUridine and APA are the major ones. HBL lab has made a series of pioneering discoveries in the m6A studies, won international reputations in the field, and laid solid experimental foundation. m6A research has been the frontier of the epigenetics field, but it is under explored for other types of RNA modifications, especially the cross-talks among those RNA modifications in response to environmental stimulation are unknown. Immune cells, especially T cells and macrophages in various inflammatory disease and tumor, provide an ideal perspective to explore this frontier. Combine mouse reverse genetics and state-of-art omics techniques, our research focuses on the following areas:

(1)  Function of m1A modification in T cells and macrophages;

(2)  Function of pseudouridine modification in T cells and macrophages;

(3)  Function of APA modification in T cells and macrophages;

(4)  Develop inhibitors to those RNA modification and apply to tumor immunotherapy;

(5)  Cross-talks of those RNA modifications.

实验室主页：https://hua-binglilab.com/

1. Zhang T#, Ding C#, Roulis M, Zhao J, Chen H, Chen Z, Chen B, Mao K, Hao Y, Xu H, Kluger Y, Zou Q, Ye Y, Flavell RA*, Li HB*. (2021) m6A mRNA modification is a rheostat to maintain colonic epithelial cell homeostasis. 2022, Science Advances, 8, eabl5723, 2022 March 25 IF: 14.136

2.Qin Y, Li B, Arumugam S, Lu Q, Mankash SM, Li J, Sun B, Li J, Flavell RA*, Li HB*, Ouyang X*. (2021) m6A mRNA methylation-directed myeloid cell activation controls progression of NAFLD and obesity. Cell Rep. 2021 Nov 9;37(6):109968. doi: 10.1016/j.celrep.2021.109968. PMID: 34758326 (^* co-corresponding)

3.Song H, Song J, Cheng M, Zheng M, Wang T, Tian S, Flavell RA, Zhu S, Li HB, Ding C, Wei H, Sun R, Peng H, Tian Z. (2021) METTL3-mediated m6A RNA methylation promotes the anti-tumour immunity of natural killer cells. Nat Commun, 2021 Sep 17;12(1):5522. doi: 10.1038/s41467-021-25803-0.PMID: 34535671

4.Zhou J#, Zhang X#, Hu J, Qu R, Yu Z, Xu H, Chen H, Yan L, Ding C, Zou Q, Ye Y, Wang Z, Flavell RA*, Li HB*. (2021) m6A Demethylase ALKBH5 Controls CD4+ T cell Pathogenicity and Promotes Autoimmunity.Science Advances, 2021 Jun 16;7(25):eabg0470. doi: 10.1126/sciadv.abg0470. PMID: 34134995 (^* co-corresponding)

5.Chao Y, Li HB*, Zhou J*. Multiple Functions of RNA Methylation in T Cells: A Review. Front Immunol. 2021 Apr 12;12:627455. doi: 10.3389/fimmu.2021.627455. eCollection 2021. PMID: 33912158(^* co-corresponding)

6.Tong J#, Wang X#, Liu Y#, Ren X, Wang A, Chen Z, Yao J, Mao K, Liu T, Meng FL, Pan W, Zou Q, Zhou Y, Xia Q*, Flavell RA*,Zhu S*, Li HB*. (2021) Pooled CRISPR Screening Identifies m6A as a Positive Regulator of Macrophage Activation. Science Advances, 2021 Apr 28;7(18):eabd4742. doi: 10.1126/sciadv.abd4742.PMID: 33910903(^* co-corresponding)

7.Wu N, Sun H, Zhao X, Zhang Y, Tan J, Qi Y, Wang Q, Ng M, Liu Z, He L, Niu X, Chen L, Liu Z,Li HB, Zeng YA, Roulis M, Liu D, Cheng J, Zhou B, Ng LG, Zou D, Ye Y, Flavell RA, Ginhoux F, Su B. MAP3K2-regulated intestinal stromal cells define a distinct stem cell niche. Nature. 2021 Apr;592(7855):606-610. doi: 10.1038/s41586-021-03283-y. Epub 2021 Mar 3. PMID: 33658717

8.Chen H#, Yao J#, Bao R, Dong Y, Zhang T, Du Y, Wang G, Ni D, Xun Z, Niu X, Ye Y*,Li HB*. (2021) Cross-talk of Four Types of RNA Modification Writers Defines Tumor Microenvironment and Pharmacogenomic Landscape in Colorectal Cancer. Molecular Cancer20(1):29. doi: 10.1186/s12943-021-01322-w.PMID: 33557837(^* co-corresponding)

9.Wang Y#, He K#, Sheng B#, Lei X, Tao WE, Zhu X, Wei Z, Fu R, Wang A, Bai S, Zhang Z, Hong N, Ye C, Tian Y, Wang J, Li M, Zhang K, Li L, Yang H*, Li HB*, Flavell RA*, Zhu S*. (2021) The RNA helicase Dhx15 mediates Wnt-induced anti-microbial protein expression in Paneth cells. Proc. Natl. Acad. Sci. U.S.A.,118 (4) e2017432118(^* co-corresponding)

10.Xu C*, Li HB*, Flavell RA*. A special collection of reviews on frontiers in immunology. Cell Research. Oct;30(10):827-828. doi: 10.1038/s41422-020-00403-7. ^* (co-corresponding, Editorial)

11.Gao Y*#, Vasic R#, Song Y#, Teng R, Gbyli R, Biancon G, Nelakanti R, Liu C, Kudo E, Lobben K, Liu W, Ardasheva A, Fu X, Wang X, Joshi P, Lee V, Dura B, Viero G, Iwasaki A, Fan R, Xiao A, Flavell RA*, Li HB*, Tebaldi T*, Halene S*. (2020) Activation of Double-Stranded RNA Innate Immune Response and Hematopoietic Failure upon Loss of METTL3-Mediated m6A RNA Modification. Immunity. 2020 Jun 16;52(6):1007-1021.e8. doi: 10.1016/j.immuni.2020.05.003. Epub 2020 Jun 3. PMID: 32497523(^* co-corresponding)

12. Hwang SS, Lim J, Yu Z, Kong P, Sefik E, Xu H, Harman CCD, Kim LK, Lee GR,Li HB, Flavell RA.(2020) mRNA destabilization by BTG1 and BTG2 maintains T cell quiescence.Science. 2020 Mar 13;367(6483):1255-1260. doi: 10.1126/science.aax0194. PMID: 32165587

13.Zhang X, Flavell RA*, Li HB*.(2019) hnRNPA2B1: a nuclear DNA sensor in antiviral immunity.Cell Research. 2019 Nov;29(11):879-880. doi: 10.1038/s41422-019-0226-8.

14.Wang J, Flavell RA*, Li HB*. (2019) Antiviral immunity: a link to bile acids.Cell Research, 2019 Mar;29(3):177-178. doi: 10.1038/s41422-019-0148-5. PMID: 30778178 (* co-corresponding)

15.Liu Y, Li HB*, Flavell RA*. (2018) cGAS activation in phased droplets. Cell Research, 2018 Oct;28(10):967-968. doi: 10.1038/s41422-018-0087-6.PMID: 30218060 (* co-corresponding)

16.Yu X, Teng XL, Wang F, Zheng Y, Qu G, Zhou Y, Hu Z, Wu Z, Chang Y, Chen L, Li HB, Su B, Lu L, Liu Z, Sun SC, Zou Q. (2018) Metabolic control of regulatory T cell stability and function by TRAF3IP3 at the lysosome. J Exp Med. 2018 Sep 3;215(9):2463-2476. doi: 10.1084/jem.20180397. PMID: 30115741

17.Tong J, Flavell RA*, Li HB*. (2018) RNA m6A modification and its functions in diseases. Frontiers of Medicine, 2018 Aug;12(4):481-489. doi: 10.1007/s11684-018-0654-8.PMID: 30097961 (* co-corresponding)

18.Yu X, Lao Y, Teng XL, Li S, Zhou Y, Wang F, Guo X, Deng S, Chang Y, Wu X, Liu Z, Chen L, Lu LM, Cheng J, Li B, Su B, Jiang J, Li HB*, Huang C*, Yi J*, Zou Q*. (2018) SENP3 maintains the stability and function of regulatory T cells via BACH2 deSUMOylation. Nature Communications. 2018 Aug 8;9(1):3157. doi: 10.1038/s41467-018-05676-6. PMID: 30089837 (* co-corresponding)

19.Tong J#, Cao G#, Zhang T#, Sefik E, Vesely M, Broughton J, Zhu S, Li H, Li B, Chen L, Chang HY, Su B, Flavell RA*, Li HB*. (2018) m6A mRNA methylation sustains Treg suppressive functions. Cell Research, 28(2): 253-256. doi:10.1038/cr.2018.7. PMID: 29303144 (*co-corresponding)

20.Li HB#*, Tong J#, Zhu S#, Batista PJ, Duffy EE, Zhao J, Bailis W, Cao G, Kroehling L, Chen Y, Wang G, Broughton JP, Chen YG, Kluger Y, Simon MD, Chang HY, Yin Z*, Flavell RA*. (2017) m6A mRNA methylation controls T cell homeostasis by targeting IL-7/STAT5/SOCS pathway. Nature. 2017 Aug 17;548(7667):338-342. doi: 10.1038/nature23450. Epub 2017 Aug 9.. PMID: 28792938 (# equal contribution, * co-corresponding)

21.Zhu S, Ding S, Wang P, Wei Z,      Pan W, Palm NW, Yang Y, Yu H, Li HB,Wang G, Lei X, de Zoete MR,      Zhao J, Zheng Y, Chen H, Zhao Y, Jurado KA, Feng N, Shan L, Kluger Y, Lu      J, Abraham C, Fikrig E, Greenberg HB, Flavell RA. (2017) Nlrp9b      inflammasome recognizes and restricts rotavirus infection in intestinal      epithelial cells. Nature, 546(7660): 667-670. doi: 10.1038/nature22967. PMID: 28636595

22.Hu B#, Jin C#, Li HB#, Tong J, Ouyang X, Cetinbas NM, Zhu S, Strowig T, Lam FC, Zhao C, Henao-Mejia J, Yilmaz O, Fitzgerald KA, Eisenbarth SC, Elinav E, Flavell RA. (2016)The DNA Sensing Aim2 Inflammasome Controls Radiation Induced Cell death and Tissue Injury. Science, 354 (6313): 765-768. DOI: 10.1126/science.aaf7532. PMID: 27846608 (# equal contribution)

23.Li HB. (2016) Chromosome Conformation Capture in Drosophila. Methods Mol. Biol. 1480:207-12. doi: 10.1007/978-1-4939-6380-5_18. PMID: 27659987

24.Cao G#, Li HB#, Yin Z, Flavell RA. (2016) Recent advances in dynamic m6A RNA modification. Open Biology. 6(4): 160003.  doi: 10.1098/rsob.160003. PMID: 27249342 (# equal contribution)

25.Zhu S#, Li HB#, Flavell RA. (2014) Resemble and Inhibit: When RLR Meets TGF-β. Mol Cell. 56(6):719-20. doi: 10.1016/j.molcel.2014.12.010. PMID: 25526529 (# equal contribution) 

26.Li HB#, Jin C#, Chen Y#, Flavell RA. (2014) Inflammasome activation and metabolic disease progression. Cytokine Growth Factor Rev. 25(6):699-706. doi: 10.1016/j.cytogfr.2014.07.020. PMID: 25156419 (# equal contribution)

27.Li HB, Ohno K, Gui H, and Pirrotta V. (2013) Insulators target active genes to transcription factories and Polycomb-repressed genes to PcG bodies. PLoS Genet.9(4):e1003436. doi: 10.1371/journal.pgen.1003436. PMID: 23637616 (Highlighted by Cell: 153(5), p935)

28.Schwartz YB, Linder-Basso D, Kharchenko PV, Tolstorukov MY, Kim M,Li HB, Gorchakov AA, Minoda A, Shanower G, Alekseyenko AA, Riddle NC, Jung YL, Gu T, Plachetka A, Elgin SC, Kuroda MI, Park PJ, Savitsky M, Karpen GH, Pirrotta V. (2012) Nature and function of insulator protein binding sites in the Drosophila genome.Genome Res.22(11): 2188-98. doi: 10.1101/gr.138156.112.PMID: 22767387

29.Pirrotta V., and Li HB(2012). A view of nuclear Polycomb bodies. Curr. Opin. Genet. Dev.22(2):101-9. doi: 10.1016/j.gde.2011.11.004. PMID: 22178420

30.Li HB, Muller M, Bahechar I, Kyrchanova O, Ohno K, Georgiev P, and Pirrotta V. (2011) Insulators, not Polycomb Response Elements, are required for long-range interactions between Polycomb targets in Drosophila. Mol. Cell. Biol. 31(4):616-25. doi: 10.1128/MCB.00849-10. PMID: 21135119