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).
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).