Retinoic acid activates HOXD4 chromatin

Stable Identifier
R-HSA-5617896
Type
Reaction [omitted]
Species
Homo sapiens
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As inferred from mouse embryos, retinoic acid activates the HOXD4 gene in rhombomere 7 (r7) by binding RARB or RARA in RAR:RXR receptor dimers bound to a retinoic acid response element (RAREs) in the 5' flanking region of the gene. Ligand binding by retinoic acid receptors causes dismissal of corepressors such as NCOR1 and recruitment of coactivators such as NCOA3 (Klein et al. 2000). The response of HOXD4 to retinoic acid is also observed in human embryonal carcinoma cells (Moroni et al. 1993, Morrison et al. 1996, Morrison et al. 1997). PAX6 binds near the RARE and is required for maximal activation.
In human fibroblasts chromatin at HOXA genes is activated by loss of methylation at lysine-27 (H3K27me3), loss of Polycomb repressive complex 2 (PRC2), and gain of H3K4me3 (Lan et al. 2007). Similar changes occur at Hoxd4 in mouse embryos. The histone demethylase KDM6A (UTX) binds the HOXD4 gene in human lung fibroblasts and may participate in demethylating H3K27me3 (Lan et al. 2007). Other factors may also be involved in demethylation. KDM6A associates with the histone methyltransferases KMT2C,D (MLL2,3) which may participate in methylating H3K4 (Lee et al. 2007). As inferred from mouse homologs, PCGF2 (MEL18) dissociates from Hoxd4 during activation. After activation by retinoic acid, HOXD4 maintains its own expression by binding and activating its own promoter.

Literature References
PubMed ID Title Journal Year
17851529 A histone H3 lysine 27 demethylase regulates animal posterior development

Lan, F, Bayliss, PE, Rinn, JL, Whetstine, JR, Wang, JK, Chen, S, Iwase, S, Alpatov, R, Issaeva, I, Canaani, E, Roberts, TM, Chang, HY, Shi, Y

Nature 2007
9272954 HOXD4 and regulation of the group 4 paralog genes

Morrison, A, Ariza-McNaughton, L, Gould, A, Featherstone, M, Krumlauf, R

Development 1997
7908827 Regulation of the human HOXD4 gene by retinoids

Moroni, MC, ViganĂ³, MA, Mavilio, F

Mech. Dev. 1993
10777502 Recruitment of nuclear receptor corepressor and coactivator to the retinoic acid receptor by retinoid ligands. Influence of DNA-heterodimer interactions

Klein, ES, Wang, JW, Khalifa, B, Gavigan, SA, Chandraratna, RA

J. Biol. Chem. 2000
8674428 In vitro and transgenic analysis of a human HOXD4 retinoid-responsive enhancer

Morrison, A, Moroni, MC, Ariza-McNaughton, L, Krumlauf, R, Mavilio, F

Development 1996
22879880 Functional dissection of HOXD cluster genes in regulation of neuroblastoma cell proliferation and differentiation

Zha, Y, Ding, E, Yang, L, Mao, L, Wang, X, McCarthy, BA, Huang, S, Ding, HF

PLoS ONE 2012
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