Retinoic acid activates the Hoxb4 gene in rhombomere 7 (r7) by binding the retinoic acid receptor Rarb (Folberg et al. 1999) and perhaps Rara in Rar:Rxr dimers bound to retinoic acid response elements (RAREs) located in the 3' flanking region of the Hoxb4 gene (Morrison et al. 1997, Gould et al. 1998), causing dissociation of corepressors and recruitment of coactivators (inferred from Hoxa1, Gillespie and Gudas 2007, Kashyap and Gudas 2010). Hoxb4 maintains its own expression by binding and activating its own promoter (Gould et al. 1997, Serpente et al. 2005).
In embryonic stem cells treated with retinoic acid (Kashyap et al. 2011, Mazzoni et al. 2013) and in human cells, activation of chromatin at the Hoxb4 gene is due to loss of methylation of lysine-27 at histone H3 (H3K27me3, Kashyap et al. 2011, Mazzoni et al. 2013), loss of Polycomb repressive complex 2 (PRC2, Mazzoni et al. 2013), and gain of H3K4me3 (Kashyap et al. 2011). The Mll1 and Mll2 complexes methylate H3K4 at Hoxb4 in fibroblasts (Wang et al. 2009). In human cells the histone demethylase KDM6A (UTX) binds the HOXB4 gene and participates in demethylating H3K27me3. Other factors may be involved in demethylation (Shpargel et al. 2014).