RNA Modification in Inflammatory Bowel Diseases

Nakayama, Mika; Ozato, Yuki; Tsuji, Yoshiko; Arao, Yasuko; Otsuka, Chihiro; Hamano, Yumiko; Sumi, Genzo; Ofusa, Ken; Uchida, Shizuka; Vecchione, Andrea; Ishii, Hideshi

doi:10.3390/biomedicines10071695

Cited by 5 publications

References 93 publications

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Expression profiles of the lncRNA antisense GAS5-AS1 in colon biopsies from pediatric inflammatory bowel disease patients and its role in regulating sense transcript GAS5

Curci,

Franzin,

Zudeh

et al. 2024

Eur J Pediatr

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The long non-coding RNA (lncRNA) growth arrest-specific transcript 5 (GAS5) level was demonstrated as involved in pediatric inflammatory bowel disease (IBD) pathogenesis. Since its antisense transcript GAS5-AS1 has never been investigated in IBD, this study aims to detect whether GAS5-AS1 and GAS5 levels are related to IBD clinical parameters and investigate their correlation in vitro. Twenty-six IBD pediatric patients were enrolled; paired inflamed and non-inflamed intestinal biopsies were collected. We evaluated GAS5 and GAS5-AS1 levels by real-time PCR. The role of GAS5 and GAS5-AS1 was assessed in vitro by transient silencing in THP1-derived macrophages. GAS5-AS1 and GAS5 levels were associated with patients’ clinical parameters; GAS5-AS1 expression was downregulated in inflamed tissues and inversely correlated with disease activity. A positive correlation between GAS5-AS1 and GAS5 levels was observed in non-inflamed biopsies. On THP1-derived macrophages, a reduced amount of both GAS5-AS1 and GAS5 was observed; accordingly, matrix metalloproteinase (MMP) 9 was increased. After GAS5-AS1 silencing, a downregulation of GAS5 was found, whereas no effect was detected on GAS5-AS1 after GAS5 silencing. Conclusion: This study provided for the first time new insights into the potential role of GAS5-AS1 in IBD. GAS5-AS1 modulates GAS5 levels in vitro and may serve as a potential IBD diagnostic biomarker. What is Known:• GAS5 is involved in regulating intestinal MMP-2 and MMP-9 in pediatric patients with IBD;• GAS5-AS1 has never been investigated in the context of IBD;• GAS5-AS1 regulates the expression of GAS5, increasing its stability in tissues and in vitro cell models of cancer. What is New:• GAS5-AS1 correlated with GAS5 and IBD clinical parameters;• GAS5-AS1 can modulate GAS5 levels in macrophages;• GAS5-AS1 may serve as potential IBD diagnostic biomarker.

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Expression profiles of the lncRNA antisense GAS5-AS1 in colon biopsies from pediatric inflammatory bowel disease patients and its role in regulating sense transcript GAS5

Curci,

Franzin,

Zudeh

et al. 2024

Eur J Pediatr

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Fat and proteolysis due to methionine, tryptophan, and niacin deficiency leads to alterations in gut microbiota and immune modulation in inflammatory bowel disease

Hara,

Meng,

Motooka

et al. 2024

Cancer Science

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Inflammatory bowel disease (IBD) is one of the intractable diseases. Nutritional components associated with IBD have been identified, and it is known that excessive methionine intake exacerbates inflammation, and that tryptophan metabolism is involved in inflammation. Analysis of the gut microbiota has also progressed, where Lactobacillus regulate immune cells in the intestine and suppress inflammation. However, whether the methionine and tryptophan metabolic pathways affect the growth of intestinal Lactobacillus is unknown. Here we show how transient methionine, tryptophan, and niacin deficiency affects the host and gut microbiota in mouse models of colitis (induced by dextran sodium sulfate) fed a methionine‐deficient diet (1K), tryptophan and niacin‐deficient diet (2K), or methionine, tryptophan, and niacin‐deficient diet (3K). These diets induced body weight decrease and 16S rRNA analysis of mouse feces revealed the alterations in the gut microbiota, leading to a dramatic increase in the proportion of Lactobacillus in mice. Intestinal RNA sequencing data confirmed that the expression of several serine proteases and fat‐metabolizing enzymes were elevated in mice fed with methionine, tryptophan, and niacin (MTN) deficient diet. In addition, one‐carbon metabolism and peroxisome proliferator‐activated receptor (PPAR) pathway activation were also induced with MTN deficiency. Furthermore, changes in the expression of various immune‐related cytokines were observed. These results indicate that methionine, tryptophan, and niacin metabolisms are important for the composition of intestinal bacteria and host immunity. Taken together, MTN deficiencies may serve as a Great Reset of gut microbiota and host gene expression to return to good health.

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

Castellanos-Rubio,

Rojas-Marquez,

Olazagoitia-Garmendia

et al. 2023

Preprint

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Inflammatory bowel disease is a chronic inflammatory disorder of the intestine that develops in genetically susceptible individuals and which etiology remains unknown. Long non-coding RNAs (lncRNAs) have emerged as tissue-specific regulators of inflammation. In addition, m6A methylation modulates gene expression in an allele-specific manner, particularly in the context of single nucleotide polymorphisms (SNPs). Here, we describe the molecular anti-inflammatory mechanism of the lncRNA WAKMAR2 in intestinal epithelial cells. WAKMAR2 undergoes allele-specific m6A methylation, altering the binding of NOVA1 protein and reducing the expression of WAKMAR2 long isoform which ultimately enables NF-κB activation and downstream CXCL8 induction. The correlation between longWAKMAR2 and CXCL8 levels in intestinal inflammation was confirmed using human biopsy samples from intestinal inflammatory bowel disease patients and controls. Moreover, augmenting longWAKMAR2 ex vivo using an organ culture intestinal system resulted in an amelioration of inflammation. These data point to an involvement of WAKMAR2 in the induction CXCL8 in intestinal epithelial cells and in the development of IBD characteristic intestinal inflammation, explaining genetic susceptibility and providing a novel potential target for therapeutic interventions.

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RNA Modification in Inflammatory Bowel Diseases

Cited by 5 publications

References 93 publications

Expression profiles of the lncRNA antisense GAS5-AS1 in colon biopsies from pediatric inflammatory bowel disease patients and its role in regulating sense transcript GAS5

Expression profiles of the lncRNA antisense GAS5-AS1 in colon biopsies from pediatric inflammatory bowel disease patients and its role in regulating sense transcript GAS5

Fat and proteolysis due to methionine, tryptophan, and niacin deficiency leads to alterations in gut microbiota and immune modulation in inflammatory bowel disease

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

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