Volume 33, No 5, May 2023

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 33 Issue 5, May 2023: 372-388   |  Open Access

ORIGINAL ARTICLES

A lncRNA from an inflammatory bowel disease risk locus maintains intestinal host-commensal homeostasis

Hongdi Ma^1,2,† , Taidou Hu^1,2,† , Wanyin Tao^1,2 , Jiyu Tong³ , Zili Han^1,2 , Dietmar Herndler-Brandstetter³ , Zheng Wei³ , Ruize Liu⁴ , Tingyue Zhou^1,2 , Qiuyuan Liu⁵ , Xuemei Xu¹ , Kaiguang Zhang¹ , Rongbin Zhou² , Judy H. Cho⁶ , Hua-Bing Li^7,* , Hailiang Huang^4,* , Richard A. Flavell^3,8,* , Shu Zhu^1,2,9,10,*

¹Department of Digestive Disease, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
²Institute of Immunology, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
³Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
⁴Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
⁵The Key Laboratory of Digestive Diseases of Anhui Province, Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
⁶Department of Genetics, Yale School of Medicine, New Haven, CT, USA
⁷Shanghai Institute of Immunology, Department of Microbiology and Immunology, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, China
⁸Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA
⁹School of Data Science, University of Science and Technology of China, Hefei, Anhui, China
¹⁰Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, Anhui, China
^†These authors contributed equally: Hongdi Ma, Taidou Hu
Correspondence: Hua-Bing Li(huabing.li@shsmu.edu.cn)Hailiang Huang(hhuang@broadinstitute.org)Richard A. Flavell(richard.flavell@yale.edu)Shu Zhu(zhushu@ustc.edu.cn)

Inflammatory bowel diseases (IBD) are known to have complex, genetically influenced etiologies, involving dysfunctional interactions between the intestinal immune system and the microbiome. Here, we characterized how the RNA transcript from an IBD-associated long non-coding RNA locus (“CARINH-Colitis Associated IRF1 antisense Regulator of Intestinal Homeostasis”) protects against IBD. We show that CARINH and its neighboring gene coding for the transcription factor IRF1 together form a feedforward loop in host myeloid cells. The loop activation is sustained by microbial factors, and functions to maintain the intestinal host-commensal homeostasis via the induction of the anti-inflammatory factor IL-18BP and anti-microbial factors called guanylate-binding proteins (GBPs). Extending these mechanistic insights back to humans, we demonstrate that the function of the CARINH/IRF1 loop is conserved between mice and humans. Genetically, the T allele of rs2188962, the most probable causal variant of IBD within the CARINH locus from the human genetics study, impairs the inducible expression of the CARINH/IRF1 loop and thus increases genetic predisposition to IBD. Our study thus illustrates how an IBD-associated lncRNA maintains intestinal homeostasis and protects the host against colitis.

https://doi.org/10.1038/s41422-023-00790-7

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