Mucosal transcriptomics highlight lncRNAs implicated in ulcerative colitis, Crohn’s disease, and celiac disease

Abstract

Ulcerative colitis (UC), Crohn's disease (CD), and celiac disease are prevalent intestinal inflammatory disorders with nonsatisfactory therapeutic interventions. Analyzing patient data-driven cohorts can highlight disease pathways and new targets for interventions. Long noncoding RNAs (lncRNAs) are attractive candidates, since they are readily targetable by RNA therapeutics, show relative cell-specific expression, and play key cellular functions. Uniformly analyzing gut mucosal transcriptomics from 696 subjects, we have highlighted lncRNA expression along the gastrointestinal (GI) tract, demonstrating that, in control samples, lncRNAs have a more location-specific expression in comparison with protein-coding genes. We defined dysregulation of lncRNAs in treatment-naive UC, CD, and celiac diseases using independent test and validation cohorts. Using the Predicting Response to Standardized Pediatric Colitis Therapy (PROTECT) inception UC cohort, we defined and prioritized lncRNA linked with UC severity and prospective outcomes, and we highlighted lncRNAs linked with gut microbes previously implicated in mucosal homeostasis. HNF1A-AS1 lncRNA was reduced in all 3 conditions and was further reduced in more severe UC form. Similarly, the reduction of HNF1A-AS1 ortholog in mice gut epithelia showed higher sensitivity to dextran sodium sulfate-induced colitis, which was coupled with alteration in the gut microbial community. These analyses highlight prioritized dysregulated lncRNAs that can guide future preclinical studies for testing them as potential targets.

Challenges in Defining a Reference Set of Differentially Expressed lncRNAs in Ulcerative Colitis by Meta-Analysis

“…Information about tissue biopsy location, medication, gender, and age were not listed in some datasets. Different tissue locations have been shown to influence lncRNA expression profiles [35,36]; unfortunately, subgrouping by available tissue location would lead to groups that were too small for a robust statistical analysis. Comparison of lncRNA expression between tissue types could lead to erroneous interpretations depicted in Figure 2.…”

“…Comparison of lncRNA expression between tissue types could lead to erroneous interpretations depicted in Figure 2. A recent review of lncRNA mucosal transcripts implicated in UC, Crohn's disease, and celiac disease revealed that the lncRNAs showed significantly more location-specific expression along the GI tract than the protein-coding genes [36]. Comparing tissue types directly could lead to a more comprehensive set of tissue-specific differentially expressed lncRNAs in UC.…”

“…The expression pattern of these lncRNAs is consistent with our findings (Figure S2). LncRNAs CDKN2B-AS1, CRNDE, DPP10-AS1, and GATA6-AS1 have been studied in the context of UC, with documented roles in various functions, including maintaining intestinal barrier integrity and modulating inflammation during the progression of UC [5,20,36,48]. A recent study has demonstrated an association between reduced GATA6-AS1 expression and increased UC severity, as well as an unfavorable clinical outcome.…”

m6A modified lncRNA WAKMAR2 induces intestinal inflammation through an allele-specific RNA methylation dependent splicing mechanism

“…Other lncRNAs such as LOC339803 or Lnc-UC have been speci cally associated with the development of in ammation in IBD (9,10). Furthermore, a recent transcriptome study of the intestinal mucosa have identi ed several dysregulated lncRNAs, including WAKMAR2, in IBD and celiac disease with a highly tissue-dependent expression patterns (14). Additionally, WAKMAR2 has previously been linked to other in ammatory pathologies as rheumatoid arthritis, psoriasis or chronic dermatitis (26, 29, 30), highlighting the importance of lncRNAs in in ammatory disorders (31).…”

“…Interestingly, recent studies have demonstrated that some lncRNAs have a more location speci c expression in the GI tract than coding genes, suggesting they may serve as prognostic markers and also as potential targets to improve disease outcome (14). Among these lncRNAs, WAKMAR2, previously related to in ammation in keratinocytes, is present on chromosome 6 (q23.6) and harbors an IBD associated SNP within its sequence (rs5029924) (15).…”