Body-wide genetic deficiency of poly(ADP-ribose) polymerase 14 sensitizes mice to colitis
Inflammatory bowel disease (IBD) is a debilitating and relapsing chronic disease of the gastrointestinal tract affecting millions of people. Here, we investigated the expression and functions of poly (ADP-ribose) polymerase 14 (Parp14), an important regulator of immune cells functions, using a biobank IBD patient cohort as well as the oral dextran sulfate sodium (DSS) exposure mouse IBD colitis, and, in parallel, the oral Salmonella exposure mouse colitis models. Parp14 was expressed in the human colon, by cells in the lamina propria, but, in particular, by the epithelial cells with a typical granular staining pattern in the cytosol. The same Parp14 staining pattern was evidenced in both mouse models. Body-wide genetic deficiency of Parp14 in C57BL/6N background sensitized mice to DSS colitis, i.e., the Parp14-deficient mice displayed increased rectal bleeding as well as stronger epithelial erosion, Goblet cell loss and immune cell infiltration. The absence of Parp14 did not cause mouse colon bacterial dysbiosis based on PacBio long read sequencing. Also, the colon leukocyte populations of Parp14-deficient mice appeared nominal based on flow cytometry. In contrast, we witnessed an altered transcriptional signature in Parp14-deficient mice with bulk tissue RNA-Seq. Gene Ontology (GO)-based classification of differentially expressed genes demonstrated that the colon transcriptional signature of Parp14-deficient mice was dominated by abnormalities in inflammation and infection response both prior and after the DSS exposure. The data indicate that Parp14 has an important role in the maintenance of epithelial barrier integrity in colitis, and that Parp14 may have functions also outside the immune cell compartment. The prognostic and predictive biomarker potential of Parp14 as well as its mutational landscape in IBD merits further investigation. Overall design: To investigate the transcriptome changes in colon of Parp14-deficient mice when compared to wt mice in resting state and post DSS-induced colitis, we performed bulk tissue RNA-Seq analysis of the mouse colon distal sections post-DSS treatment at day 8.