Rohde Magdalena, Sievers Elisabeth, Janzer Andreas, Willmann Dominica, Egert Angela, Schorle Hubert, Schüle Roland, Kirfel Jutta
Institute of Pathology, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany.
Urologische Klinik/Frauenklinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Breisacherstrasse 66, 79106 Freiburg, Germany.
Exp Cell Res. 2016 Nov 1;348(2):123-131. doi: 10.1016/j.yexcr.2016.08.026. Epub 2016 Sep 17.
Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing, immune responses and invasive tumors all require the orchestrated movement of cells to specific locations. Histone demethylase proteins alter transcription by regulating the chromatin state at specific gene loci. FBXL10 is a conserved and ubiquitously expressed member of the JmjC domain-containing histone demethylase family and is implicated in the demethylation of H3K4me3 and H3K36me2 and thereby removing active chromatin marks. However, the physiological role of FBXL10 in vivo remains largely unknown. Therefore, we established an inducible gain of function model to analyze the role of Fbxl10 and compared wild-type with Fbxl10 overexpressing mouse embryonic fibroblasts (MEFs). Our study shows that overexpression of Fbxl10 in MEFs doesn't influence the proliferation capability but leads to an enhanced migration capacity in comparison to wild-type MEFs. Transcriptome and ChIP-seq experiments demonstrated that Fbxl10 binds to genes involved in migration like Areg, Mdk, Lmnb1, Thbs1, Mgp and Cxcl12. Taken together, our results strongly suggest that Fbxl10 plays a critical role in migration by binding to the promoter region of migration-associated genes and thereby might influences cell behaviour to a possibly more aggressive phenotype.
细胞迁移是多细胞生物体发育和维持过程中的核心过程。胚胎发育过程中的组织形成、伤口愈合、免疫反应和侵袭性肿瘤都需要细胞有组织地移动到特定位置。组蛋白去甲基化酶蛋白通过调节特定基因位点的染色质状态来改变转录。FBXL10是含JmjC结构域的组蛋白去甲基化酶家族中一个保守且广泛表达的成员，与H3K4me3和H3K36me2的去甲基化有关，从而去除活性染色质标记。然而，FBXL10在体内的生理作用在很大程度上仍然未知。因此，我们建立了一个可诱导的功能获得模型来分析Fbxl10的作用，并将野生型小鼠胚胎成纤维细胞（MEFs）与过表达Fbxl10的MEFs进行比较。我们的研究表明，与野生型MEFs相比，MEFs中Fbxl10的过表达不会影响增殖能力，但会导致迁移能力增强。转录组和ChIP-seq实验表明，Fbxl10与Areg、Mdk、Lmnb1、Thbs1、Mgp和Cxcl12等参与迁移的基因结合。综上所述，我们的结果强烈表明，Fbxl10通过与迁移相关基因的启动子区域结合在迁移中起关键作用，从而可能影响细胞行为，使其呈现出可能更具侵袭性的表型。
