IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), INSERM, U964, CNRS, UMR7104, Université de Strasbourg, 1 rue Laurent Fries, BP 10142, 67404 Illkirch Cedex, France.
J Cell Sci. 2014 Feb 1;127(Pt 3):521-33. doi: 10.1242/jcs.131946. Epub 2013 Dec 19.
Nuclear retinoic acid (RA) receptors (RARα, β and γ) are ligand-dependent transcription factors that regulate the expression of a battery of genes involved in cell differentiation and proliferation. They are also phosphoproteins and we previously showed the importance of their phosphorylation in their transcriptional activity. In the study reported here, we conducted a genome-wide analysis of the genes that are regulated by RARs in mouse embryonic fibroblasts (MEFs) by comparing wild-type MEFs to MEFs lacking the three RARs. We found that in the absence of RA, RARs control the expression of several gene transcripts associated with cell adhesion. Consequently the knockout MEFs are unable to adhere and to spread on substrates and they display a disrupted network of actin filaments, compared with the WT cells. In contrast, in the presence of the ligand, RARs control the expression of other genes involved in signaling and in RA metabolism. Taking advantage of rescue cell lines expressing the RARα or RARγ subtypes (either wild-type or mutated at the N-terminal phosphorylation sites) in the null background, we found that the expression of RA-target genes can be controlled either by a specific single RAR or by a combination of RAR isotypes, depending on the gene. We also selected genes that require the phosphorylation of the receptors for their regulation by RA. Our results increase the repertoire of genes that are regulated by RARs and highlight the complexity and diversity of the transcriptional programs regulated by RARs, depending on the gene.
核视黄酸（RA）受体（RARα、β 和 γ）是配体依赖性转录因子，可调节参与细胞分化和增殖的一系列基因的表达。它们也是磷酸化蛋白，我们之前已经证明了它们的磷酸化在其转录活性中的重要性。在本报告中，我们通过比较野生型 MEF（小鼠胚胎成纤维细胞）和缺乏三种 RAR 的 MEF，对 RAR 调节的基因进行了全基因组分析。我们发现，在没有 RA 的情况下，RAR 控制着与细胞黏附相关的几个基因转录本的表达。因此，与 WT 细胞相比，敲除 MEF 无法黏附和在基质上扩展，并且它们的肌动蛋白丝网络紊乱。相比之下，在配体存在的情况下，RAR 控制着参与信号转导和 RA 代谢的其他基因的表达。利用在缺失背景下表达 RARα 或 RARγ 亚型（野生型或 N 端磷酸化位点突变）的挽救细胞系，我们发现 RA 靶基因的表达可以由特定的单个 RAR 或由 RAR 同工型的组合来控制，这取决于基因。我们还选择了需要受体磷酸化才能被 RA 调节的基因。我们的结果增加了受 RAR 调节的基因的种类，并强调了 RAR 调节的转录程序的复杂性和多样性，这取决于基因。
