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

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.

Shared genetic architecture between autoimmune disorders and B-cell acute lymphoblastic leukemia: insights from large-scale genome-wide cross-trait analysis

“…Although direct evidence of its association with ALL is lacking, increased mRNA levels have been observed in AML patients [ 96 ]. Additionally, the long non-coding RNA C5orf56 (5q31) has been identified for its protective role in IBD [ 97 ]. SCHIP1 (3q25) has been associated with SLE [ 98 ], while RNASET2 (6q27) has been identified as a risk gene for both vitiligo [ 99 ] and GD [ 100 ].…”

DHX9 maintains epithelial homeostasis by restraining R-loop-mediated genomic instability in intestinal stem cells

“…Additionally, biopsy specimens of UC for RT-qPCR analysis were obtained from the same institution. The CD biopsy specimens used for RT-qPCR analysis were derived from our previous study 68 . Detailed information of patients was show included in Supplementary Table 1 .…”

“…Slides were examined under a light microscope (BX53, Olympus), and images were captured for subsequent analysis. The histopathological score for each section was referenced to previous studies 68 , 69 . Briefly, each sample was blindly scored for four criteria: amount of inflammation (0 = none, 1 = slight, 2 = moderate, 3 = severe), extent of inflammation (0 = none, 1 = mucosa, 2 = mucosa and submucosa, 3 = transmural), regeneration (0 = complete regeneration or normal tissue, 1 = almost complete regeneration, 2 = regeneration with crypt depletion, 3 = surface epithelium not intact, 4 = no tissue repair), crypt damage (0 = none, 1 = basal 1/3 damaged, 2 = Basal 2/3 damaged, 3 = only surface epithelium intact, 4 = entire crypt and epithelium lost).…”

Research advancements and perspectives of inflammatory bowel disease: A comprehensive review

“… 25 Colitis associated interferon regulatory factor 1 (IRF1) antisense regulator of intestinal homeostasis (CARINH), a lncRNA-C5orf56 from a noncoding region, protects against IBD. 26 RNA transcript from CARINH interacts with E1A-associated protein p300/cyclic-AMP response element binding protein to promote the deposition of activating histone modifications H3K27ac at the IRF1 locus, thus increasing the expression of IRF1 for upregulating expression of interleukin 18 binding protein. 26 A study of Russian CD patients reveals that rs9858542 of bassoon presynaptic cytomatrix protein (BSN), rs3816769 of signal transducer and activator of transcription 3 (STAT3) and rs1793004 of neural epidermal growth factor-like like 1 (NELL1) are associated with a higher risk of CD, which shows a negative correlation with Bacteroidetes phylum, phylum Bacteroidetes and family Ruminococcaceae.…”

“… 26 RNA transcript from CARINH interacts with E1A-associated protein p300/cyclic-AMP response element binding protein to promote the deposition of activating histone modifications H3K27ac at the IRF1 locus, thus increasing the expression of IRF1 for upregulating expression of interleukin 18 binding protein. 26 A study of Russian CD patients reveals that rs9858542 of bassoon presynaptic cytomatrix protein (BSN), rs3816769 of signal transducer and activator of transcription 3 (STAT3) and rs1793004 of neural epidermal growth factor-like like 1 (NELL1) are associated with a higher risk of CD, which shows a negative correlation with Bacteroidetes phylum, phylum Bacteroidetes and family Ruminococcaceae. 27 Thus, genetic susceptibility to IBD may alter the composition of gut microbiota, and environmental factors may affect gene susceptibility-related inflammatory, which indicates the interactions between them play a great role in IBD pathogenesis.…”