Retinoic acid activates Hoxa4 chromatin

In mouse embryos retinoic acid initially activates expression of the Hoxa4 gene in rhombomere 7 (r7) and regions of mesoderm by binding Rarb or Rara in dimeric Rar:Rxr complexes located at retinoic acid response elements (RAREs) in the 5' flanking region of the Hoxa4 promoter (Behringer et al. 1993, Morrison et al. 1997, Packer et al. 1998, Packer et al. 2000), causing dissociation of corepressors and recruitment of corepressors (inferred from Hoxa1, Gillespie and Gudas 2007, Kashyap and Gudas 2010). Hoxa4 itself maintains later expression in an autoregulatory loop (Wu and Wolgemuth 1993, Packer et al. 1998).<br>Treatment of embryonic stem cells with retinoic acid causes loss of methylation at histone 3 lysine-27 (H3K27me3, Kashyap et al. 2011, Mazzoni et al. 2013, Shpargel et al. 2014), loss of Polycomb repressive complex 2 (PRC2, Mazzoni et al. 2013) and gain of methylation at histone 3 lysine-4 (H3K4me3, Kashyap et al. 2011) across the Hoxa gene cluster. The Mll2 complex methylates H3K4 at Hoxa4 in fibroblasts (Wang et al. 2009).

在鼠胚胎中，视黄酸最初通过结合位于Hoxa4启动子5'侧翼区域的视黄酸反应元件（RAREs）中的Rarb或Rara，在二聚体Rar:Rxr复合物的作用下激活7型菱形脊（r7）和中胚层的Hoxa4基因表达（Behringer等，1993；Morrison等，1997；Packer等，1998，2000），导致核心抑制物的解离以及核心抑制物的募集（由Hoxa1推断，Gillespie和Gudas，2007；Kashyap和Gudas，2010）。Hoxa4本身通过自调节回路维持后续的表达（Wu和Wolgemuth，1993；Packer等，1998）。视黄酸对胚胎干细胞的处理导致组蛋白3赖氨酸-27（H3K27me3，Kashyap等，2011；Mazzoni等，2013；Shpargel等，2014）的甲基化丧失，Polycomb抑制复合体2（PRC2，Mazzoni等，2013）的丧失以及Hoxa基因簇中组蛋白3赖氨酸-4（H3K4me3，Kashyap等，2011）的甲基化增加。Mll2复合物在成纤维细胞中甲基化H3K4于Hoxa4（Wang等，2009）。