Runx3 prevents spontaneous colitis by directing the differentiation of anti-inflammatory mononuclear phagocytes.
Shay HantisteanuYosef DickenVarda NegreanuDalia GoldenbergOri BrennerDena LeshkowitzJoseph LotemDitsa LevanonYoram GronerPublished in: PloS one (2020)
Mice deficient in the transcription factor Runx3 develop a multitude of immune system defects, including early onset colitis. This paper demonstrates that Runx3 is expressed in colonic mononuclear phagocytes (MNP), including resident macrophages (RM) and dendritic cell subsets (cDC2). Runx3 deletion in MNP causes early onset colitis due to their impaired maturation. Mechanistically, the resulting MNP subset imbalance leads to up-regulation of pro-inflammatory genes as occurs in IL10R-deficient RM. In addition, RM and cDC2 display a marked decrease in expression of anti-inflammatory/TGF β-regulated genes and β-catenin signaling associated genes, respectively. MNP transcriptome and ChIP-seq data analysis suggest that a significant fraction of genes affected by Runx3 loss are direct Runx3 targets. Collectively, Runx3 imposes intestinal immune tolerance by regulating maturation of colonic anti-inflammatory MNP, befitting the identification of RUNX3 as a genome-wide associated risk gene for various immune-related diseases in humans, including gastrointestinal tract diseases such as Crohn's disease and celiac.
Keyphrases
- transcription factor
- genome wide
- early onset
- genome wide identification
- anti inflammatory
- dna methylation
- late onset
- data analysis
- bioinformatics analysis
- dna binding
- copy number
- ulcerative colitis
- dendritic cells
- peripheral blood
- rna seq
- cell cycle
- single cell
- immune response
- adipose tissue
- high throughput
- epithelial mesenchymal transition
- cell proliferation
- wild type