Gene Expression Regulation Laboratory, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy.
Pathology Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy.
Nucleic Acids Res. 2023 Jun 9;51(10):5193-5209. doi: 10.1093/nar/gkad257.
The long non-coding RNA EPR is expressed in epithelial tissues, binds to chromatin and controls distinct biological activities in mouse mammary gland cells. Because of its high expression in the intestine, in this study we have generated a colon-specific conditional targeted deletion (EPR cKO) to evaluate EPR in vivo functions in mice. EPR cKO mice display epithelium hyperproliferation, impaired mucus production and secretion, as well as inflammatory infiltration in the proximal portion of the large intestine. RNA sequencing analysis reveals a rearrangement of the colon crypt transcriptome with strong reduction of goblet cell-specific factors including those involved in the synthesis, assembly, transport and control of mucus proteins. Further, colon mucosa integrity and permeability are impaired in EPR cKO mice, and this results in higher susceptibility to dextran sodium sulfate (DSS)-induced colitis and tumor formation. Human EPR is down-regulated in human cancer cell lines as well as in human cancers, and overexpression of EPR in a colon cancer cell line results in enhanced expression of pro-apoptotic genes. Mechanistically, we show that EPR directly interacts with select genes involved in mucus metabolism whose expression is reduced in EPR cKO mice and that EPR deletion causes tridimensional chromatin organization changes.
长链非编码 RNA EPR 在上皮组织中表达，与染色质结合，并在小鼠乳腺细胞中控制着不同的生物学活性。由于其在肠道中的高表达，在本研究中我们生成了一种结肠特异性条件性靶向缺失（EPR cKO），以评估 EPR 在体内的功能。EPR cKO 小鼠表现出上皮细胞过度增殖、粘液产生和分泌受损，以及大肠近端的炎症浸润。RNA 测序分析显示结肠隐窝转录组发生重排，杯状细胞特异性因子（包括参与粘液蛋白合成、组装、运输和调控的因子）强烈减少。此外，EPR cKO 小鼠的结肠黏膜完整性和通透性受损，导致对葡聚糖硫酸钠（DSS）诱导的结肠炎和肿瘤形成的易感性增加。人类 EPR 在人类癌细胞系和人类癌症中下调，并且在结肠癌细胞系中过表达 EPR 会导致促凋亡基因的表达增强。在机制上，我们表明 EPR 直接与参与粘液代谢的特定基因相互作用，这些基因在 EPR cKO 小鼠中表达减少，并且 EPR 缺失导致三维染色质组织发生变化。
