中国科学技术大学Shu Zhu，耶鲁大学医学院Richard A. Flavell，哈佛医学院Hailiang Huang和上海交通大学医学院Hua-Bing Li共同合作，近期取得重要工作进展。他们研究发现来自炎症性肠病风险基因座的lncRNA维持肠道宿主共生稳态。相关研究成果2023年4月13日在线发表于《细胞—研究》杂志上。

据介绍，炎症性肠病（IBD）具有复杂的、受遗传影响的病因，涉及肠道免疫系统和微生物组之间功能失调的相互作用。

研究人员描述了IBD相关的长非编码RNA基因座（“CARINH结肠炎相关IRF1肠道稳态反义调节因子”）的RNA转录物对IBD的保护。研究人员发现，CARINH及其编码转录因子IRF1的相邻基因在宿主髓系细胞中共同形成前馈环。环路激活由微生物因子维持，并通过诱导抗炎因子IL-18BP和称为鸟苷酸结合蛋白（GBP）的抗微生物因子来维持肠道宿主共生体内平衡。

将这些机制见解扩展到人类身上，研人员证明了CARINH/IRF1环的功能在小鼠和人类之间是保守的。从遗传学角度来看，rs2188962的T等位基因（人类遗传学研究中CARINH基因座内IBD最可能的致病变体）会削弱CARINH/IRF1环的诱导表达，从而增加IBD的遗传易感性。

因此，这一研究阐明了IBD相关的lncRNA如何维持肠道稳态并保护宿主免受结肠炎的侵袭。

附：英文原文

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

Author: Ma, Hongdi, Hu, Taidou, Tao, Wanyin, Tong, Jiyu, Han, Zili, Herndler-Brandstetter, Dietmar, Wei, Zheng, Liu, Ruize, Zhou, Tingyue, Liu, Qiuyuan, Xu, Xuemei, Zhang, Kaiguang, Zhou, Rongbin, Cho, Judy H., Li, Hua-Bing, Huang, Hailiang, Flavell, Richard A., Zhu, Shu

Issue&Volume: 2023-04-13

Abstract: 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.

DOI: 10.1038/s41422-023-00790-7

Source: https://www.nature.com/articles/s41422-023-00790-7