Meta-Biol

• Pathways

As inferred from mouse embryos and cell lines, retinoic acid binds receptors (RARA or RARG) at retinoic acid response elements (RAREs) located 3' to the HOXB1 gene, causing recruitment of coactivators such as NCOA3 and alteration of chromatin at the HOXB1 gene to an active conformation. Similar activation of the HOXB cluster by retinoic acid is observed in human embryonal carcinoma cells (Simeone et al. 1990). In human carcinoma cells and primary fibroblasts, KDM6A (UTX) binds the HOXB1 gene upon retinoic acid treatment (Agger et al. 2007, Lee et al. 2007) and may demethylate trimethylated lysine-27 of histone H3 (H3K27me3). Reduced H3K27me3 is also observed at HOXB1 in lung fibroblasts (Lan et al. 2007). Other demethylases may be redundant with KDM6A. Polycomb repressive complex 2 (PRC2), which binds H3K27me3, is also lost during activation (Lee et al. 2007). KDM6A forms complexes with the histone methyltransferase KMT2C,D (MLL2,3) which may participate in methylating histone H3 at lysine-4 (H3K4me3), an activating chromatin modification (Lee et al. 2007). After activation by retinoic acid HOXB1 maintains its own expression by binding elements in its own promoter and activating expression (Di Rocco et al. 1997).
In mouse embryos, Hoxb1 is expressed in mesoderm and neurectoderm of primitive streak stage embryos and then becomes restricted to rhombomeres of the hindbrain. Before rhombomere formation Hoxb1 is initially expressed in the region that becomes r3-7. After rhombomere formation Hoxb1 becomes restricted to r4 and is also observed in caudal mesoderm. Hoxb1 activates expression of Egr2 (Krox20), a transcription factor that subsequently activates Hoxa2, Hoxb2, and Hoxb3 and represses Hoxb1.