RNA Modification in Inflammatory Bowel Diseases

Abstract

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder characterized by damage to the intestinal mucosa, which is caused by a combination of factors. These include genetic and epigenetic alterations, environmental influence, microorganism interactions, and immune conditions. Some populations with IBD show a cancer-prone phenotype. Recent studies have provided insight into the involvement of RNA modifications in the specific pathogenesis of IBD through regulation of RNA biology in epithelial and immune cells. Studies of several RNA modification-targeting reagents have shown preferable outcomes in patients with colitis. Here, we note a new awareness of RNA modification in the targeting of IBD and related diseases, which will contribute to early diagnosis, disease monitoring, and possible control by innovative therapeutic approaches.

Keywords: RNA modification; inflammatory bowel disease.

Figure 1

Overview of the mechanism of IBD. IBD is a complex disease that develops as result of multiple factors. Previous studies have revealed that genetic and epigenetic factors are involved in the maintenance of epithelial cell homeostasis in response to intestinal bacteria, food intake, and several irritants (e.g., cigarette smoking and alcohol intake), leading to epithelial cell damage and inflammation. Cell damage and infections stimulate dendritic cells (DC) and macrophages (MP) to secrete cytokines, including IL23, resulting in the activation of the immune response of innate lymphoid cells (ILC). The immune response can induce epithelial cell damage. In IBD, inhibition or modulation of the hyper reaction of immune cells or cytokines is a therapeutic target. In this review article, we focus RNA modification in IBD, as mentioned text, figures and tables.

Figure 2

RNAs and their related molecules in human diseases. RNA polymerase-dependent synthesis and modification of mRNAs are modulated in response to the IBD microenvironment. The “writer” proteins (METTL3, METTL14, and WTAP) play a role in mRNA methylation, whereas the “eraser” proteins (FTO and ALKBH5) are involved in the removal of m⁶A methylation marks. These m⁶A marks are interpreted by “reader” proteins, such as Ythdf1, which functions in the peptide translation of mRNAs. This system plays a role in the control of peptide translation in epithelial and immune cells in IBD.

Figure 3

RNA modification mechanism in IBD. Generally, three mechanisms are involved in the activation of peptide translation of mRNAs. PTEN, phosphatase and tensin homolog; TP53, Tumor Protein P53; AKT, AKT serine/threonine kinase 1; mTORC1, mechanistic/mammalian target of rapamycin complex 1; eIF4E, eukaryotic translation initiation factor 4E; 4EBP, eukaryotic translation initiation factor 4E binding protein; eIF4G, eukaryotic translation initiation factor 4 gamma; eIF4A, eukaryotic translation initiation factor 4A; MNK1, MAPK interacting serine/threonine kinase 1; MNK2, MAPK interacting serine/threonine kinase 2; MAPK, mitogen-activated protein kinase; ERK1, mitogen activated protein kinase 3 (MAPK3); ERK2, mitogen activated protein kinase 1 (MAPK1); MEK1, MAP2K1, mitogen-activated protein kinase kinase 1; RAS, RAS proto-oncogene, GTPase; RAF, RAF-1 proto-oncogene, serine/threonine kinase.

Figure 4

RNAs, their modification and their functions in stress. Under stress (e.g., hypoxia, viral or bacterial infections), the production of tRNA-derived stress-induced RNAs (e.g., 5′-tiRNA and 3′-tiRNA) occurs via enzymatic cleavage of tRNAs. This cleavage also leads to the generation of tRNA-derived RNA fragments (tRFs), which are involved in the modulation of translation function of standard tRNAs. Several positions in tRNAs are methylated, where such methylation modulates tRNA functions.

Figure 5

Therapeutic targets of RNA modifications in IBD. In IBD, several therapeutic approaches (e.g., biological therapy, folic acid antagonist, thiopurine, 5-aminosalicylic acids (5-ASA), and steroids) have been developed to treat inflammation to control the excess reaction of the inflammatory mechanism. To control bacterial flora, antibiotics are used to inhibit or reduce pathological organisms. Cell therapy may modulate the inflammatory response of IBD. RNA modifications can be targets for the IBD mechanism to regulate altered translation and RNA processing of splicing and decay in epithelial and immune cells, which will exert synergistic effects with immune checkpoint inhibitor therapy.