Role of the ER stress protein XBP-1 in coordinating DNA damage induced inflammation and tumorigenesis in the intestinal epithelium

Doctoral Researcher

Principal Investigator

Associated Principal Investigator

Background and current state of research

So far, several risk loci are known to be predisposing for the manifestation of IBD1 many of them being involved in pathways necessary for intestinal homeostasis. One of these risk genes is the transcription factor XBP12 which initiates the Unfolded Protein Response (UPR) upon ER stress. Mice with a conditional knock-out for the intestinal Xbp1 exhibit an increased susceptibility to DSS-induced colitis and tumor development3.

It has also been reported that chronic inflammation and concomitant ER stress4 lead to the creation of ROS, which are capable of affecting the genomic integrity5. Hence it is not surprising that DNA damage is a present phenomenon in lymphocytes and intestinal epithelial cells in the context of IBD6. Preliminary studies, partly made at IKMB, point out that conditional knockout mice lacking the DNA damage repair enzyme RNaseH2b in the intestinal epithelium show an increased immune response7, especially in response to exogenous epithelial injury like in DSS colitis.

To what extent the UPR is enrolled in protective regulatory functions in response to DNA damage is not yet understood.

 

1Kaser, A., et al., Crohn's disease: NOD2, autophagy and ER stress converge. Gut, 2011; 60(11):1580-88

2Blumberg. R. S., et al., XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell. 2008; 134(5): 743–755

3Blumberg, R. S., Kaser, A., et al., ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells. J. Exp. Med., 2013;210(10):2041-56

4Blumberg. R. S., et al., The unfolded protein response in immunity and inflammation. Nature Reviews Immunology. 2016; 16(8): 469-84

5Ullmann, T.A., Itzkowitz, S.H., Intestinal inflammation and cancer. Gastroenterology, 2011; 140: 1807-1816

6Pereira, C. et al. DNA Damage and Oxidative DNA Damage in Inflammatory Bowel Disease. Journal of Crohn's and Colitis 10. 2016; 10(11):1316-1323

7Pokatayev, V., Hasin, N., et al., RNase H2 catalytic core Aicardi-Goutières syndrome-related mutant invokes cGAS-STING innate immune-sensing pathway in mice. J. Exp. Med., 2016; 213(3):329-36

Our goals

Based on previous findings underscoring an important function of RNaseH2b on genomic integrity and regenerative responses in the intestinal epithelium, we seek to explore the implications of the IBD risk gene XBP1 on DNA damage response, regeneration and differentiation in the small intestine. More specifically, we exploit mouse models of intestinal inflammation combined with in-vitro assays of cell death and proliferation.

How to get there

For in-vitro experiments with DNA-damaging agents I either use ModeK cells or organoids derived from intestinal stem cells of Xbp1∆IEC, RnaseH2b∆IEC and RnaseH2b/Xbp1∆IEC mice. These animals simultaneously deliver convenient in-vivo models for basal phenotyping, aging experiments and acute or chronic (AOM-)DSS-colitis models. Also, next generation sequencing approaches (Transcriptome, Exome Sequencing) within the in-house sequencing platform will be performed to delineate a molecular framework of DNA damage response regulated by XBP1.