Proteomic Differences in Colonic Epithelial Cells in Ulcerative Colitis Have an Epigenetic Basis

The colonic epithelium serves as both a barrier to lumenal contents and a gatekeeper of inflammatory responses. In ulcerative colitis (UC), epithelial dysfunction is a core feature, but little is known about the cellular changes that may underlie disease pathology. We therefore evaluated how the chromatin epigenetics and proteome of epithelial cells differs between health and UC.

We sorted live CD326+ epithelial cells from colon biopsies of healthy control (HC) screening colonoscopy recipients and from inflamed or uninflamed colon segments of UC patients on no biologic nor immunomodulator therapy (n = 5-7 subjects per group). Cell lysates were analyzed by proteomic evaluation and nuclei were analyzed for open chromatin with assay for transposase-accessible chromatin using sequencing.

Proteins most highly elevated in inflamed UC biopsies relative to HC were those encoded by the HLA-DRA (P = 3.1 × 10^-33) and CD74 (P = 1.6 × 10^-27), genes associated with antigen presentation, and the antimicrobial dual oxidase 2 (DUOX2) (P = 3.2 × 10^-28) and lipocalin-2 (P = 2.2 × 10^-26) genes. Conversely, the water channel aquaporin 8 was strikingly less common with inflammation (P = 1.9 × 10^-18). Assay for transposase-accessible chromatin using sequencing revealed more open chromatin around the aquaporin 8 gene in HCs (P = 2.0 × 10^-2) and more around the DUOX2/DUOXA2 locus in inflamed UC colon (P = 5.7 × 10^-4), suggesting an epigenetic basis for differential protein expression by epithelial cells in health and disease.

Numerous differences exist between the proteome and chromatin of colonic epithelial cells in UC patients and HCs, some of which correlate to suggest specific epigenetic mechanisms regulating the epithelial proteome.