Data_Sheet_1_Lnc-C/EBPβ Modulates Differentiation of MDSCs Through Downregulating IL4i1 With C/EBPβ LIP and WDR5.PDF

Myeloid-derived suppressor cells (MDSCs), which play an important role in tumor and inflammatory diseases, are divided into two subsets CD11b+Ly6ChiLy6G− monocytic MDSC (Mo-MDSC) and CD11b+Ly6Clow/negLy6G+ polymorphonuclear MDSC (PMN-MDSC) with different immunosuppressive function. However, it is poorly understood the mechanism(s) to control differentiation of Mo-MDSCs and PMN-MDSCs. Here, we found that lnc-C/EBPβ may promote PMN-MDSC but impede differentiation of Mo-MDSCs in vitro and in vivo. We demonstrated that lnc-C/EBPβ mediated differentiation of MDSCs was through downregulating multiple transcripts such as IL4il. Lnc-C/EBPβ not only bound to C/EBPβ isoform LIP to inhibit the activation of C/EBPβ but also interacted with WDR5 to interrupt the enrichment of H3K4me3 mark on the promoter region of IL4i1. Data also imply that conserved homo lnc-C/EBPβ has a similar function with mouse lnc-C/EBPβ. Since MDSC subsets exert different suppressive function, lnc-C/EBPβ may be acted as a potential therapeutic target for inflammatory and tumor-associated diseases.

髓系来源抑制细胞（Myeloid-derived suppressor cells, MDSCs）在肿瘤与炎症性疾病中发挥关键调控作用，可分为两个功能迥异的亚群：CD11b+Ly6ChiLy6G-单核细胞型髓系来源抑制细胞（monocytic MDSC, Mo-MDSC）以及CD11b+Ly6Clow/negLy6G+多形核髓系来源抑制细胞（polymorphonuclear MDSC, PMN-MDSC）。然而，目前学界对调控Mo-MDSC与PMN-MDSC分化的分子机制仍知之甚少。本研究发现，长链非编码RNA C/EBPβ（lnc-C/EBPβ）在体内外均可促进PMN-MDSC的分化，同时阻碍Mo-MDSC的分化。实验证实，lnc-C/EBPβ介导的MDSCs分化调控是通过下调IL4il等多种转录本实现的。机制研究表明，lnc-C/EBPβ不仅可结合C/EBPβ亚型LIP以抑制C/EBPβ的活化，还能与WD重复域蛋白5（WDR5）相互作用，进而阻断组蛋白H3赖氨酸4三甲基化（H3K4me3）修饰在IL4i1启动子区域的富集。数据同时提示，保守的人源lnc-C/EBPβ与小鼠源lnc-C/EBPβ具有相似的生物学功能。鉴于MDSC亚群发挥差异化的免疫抑制功能，lnc-C/EBPβ有望成为炎症性疾病及肿瘤相关疾病的潜在治疗靶点。