Waiting in the wings: RUNX3 reveals hidden depths of immune regulation with potential implications for inflammatory bowel disease

Abstract

Background Complex interactions between the environment and the mucosal immune system underlie inflammatory bowel disease (IBD). The involved cytokine signalling pathways are modulated by a number of transcription factors, one of which is runt‐related transcription factor 3 (RUNX3). Objective To systematically review the immune roles of RUNX3 in immune regulation, with a focus on the context of IBD. Methods Relevant articles and reviews were identified through a Scopus search in April 2020. Information was categorized by immune cell types, analysed and synthesized. IBD transcriptome data sets and FANTOM5 regulatory networks were processed in order to complement the literature review. Results The available evidence on the immune roles of RUNX3 allowed for its description in twelve cell types: intraepithelial lymphocyte, Th1, Th2, Th17, Treg, double‐positive T, cytotoxic T, B, dendritic, innate lymphoid, natural killer and macrophages. In the gut, the activity of RUNX3 is multifaceted and context‐dependent: it may promote homeostasis or exacerbated reactions via cytokine signalling and regulation of receptor expression. RUNX3 is mostly engaged in pathways involving ThPOK, T‐bet, IFN‐γ, TGF‐β/IL‐2Rβ, GATA/CBF‐β, SMAD/p300 and a number of miRNAs. RUNX3 targets relevant to IBD may include RAG1, OSM and IL‐17B. Moreover, in IBD RUNX3 expression correlates positively with GZMM, and negatively with IFNAR1, whereas in controls, it strongly associates with TGFBR3. Conclusions Dysregulation of RUNX3, mostly in the form of deficiency, likely contributes to IBD pathogenesis. More clinical research is needed to examine RUNX3 in IBD.

Immune cell-specific smoking-related expression characteristics are revealed by re-analysis of transcriptomes from the CEDAR cohort

“…Clec4A4 can bind antigens and participates in TLR-mediated activation of CD8α − dendritic cells, which induce a CD8 + T cell cytotoxic response under inflammatory conditions [45][46][47]. Of note, this might be related to rUnx3, the dysregulation of which in CD8 + cells (via DNA hypermethylation) also contributes to inflammatory diseases [48].…”

Immune cells and their related genes provide a new perspective on the common pathogenesis of ankylosing spondylitis and inflammatory bowel diseases

“…RUNX3, like STAT4, belongs to transcription factors and served as a prominent regulator of multiple hematopoietic cell lineages, including CD8+ T cells, T helpers, natural killers, and B cells ( 43 ). According to a systematic review, the dysregulation of RUNX3, mostly in the form of deficiency, likely contributed to IBD pathogenesis ( 44 ).…”

Methylation of RUNX3 Promoter 2 in the Whole Blood of Children with Ulcerative Colitis

“…Runt-related transcription factor 3 ( RUNX3 ) reveals functional duality in the pathogenesis of inflammatory bowel disease [ 18 ]. It is predominantly expressed in hematopoietic lineages and transcribed from two promoters: P1 that is distal and CpG-poor, and P2 which is located proximally within a conserved CpG [ 11 , 19 , 20 ].…”

“…Methylation of promoter CpG sites may lead to RUNX3 transcriptional silencing. Subsequently, dysregulation of RUNX3-associated pathways disrupts the immune cells’ development, responses, or inflammatory cytokines synthesis [ 10 , 18 ]. In this work, we described changes in local DNA methylation at RUNX3 P2 in the whole blood of 64 children with UC.…”