Reactome: A Curated Pathway Database

Retinoic acid activates Hoxb4 chromatin

Stable Identifier
Reaction [BlackBoxEvent]
Mus musculus

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).

Literature References
PubMed ID Title Journal Year
9106661 Positive cross-regulation and enhancer sharing: two mechanisms for specifying overlapping Hox expression patterns Genes Dev. 1997
9272954 HOXD4 and regulation of the group 4 paralog genes Development 1997
17663992 Retinoid regulated association of transcriptional co-regulators and the polycomb group protein SUZ12 with the retinoic acid response elements of Hoxa1, RARbeta(2), and Cyp26A1 in F9 embryonal carcinoma cells J. Mol. Biol. 2007
20231276 Epigenetic regulatory mechanisms distinguish retinoic acid-mediated transcriptional responses in stem cells and fibroblasts J. Biol. Chem. 2010
19703992 Global analysis of H3K4 methylation defines MLL family member targets and points to a role for MLL1-mediated H3K4 methylation in the regulation of transcriptional initiation by RNA polymerase II Mol. Cell. Biol. 2009
21087926 Epigenomic reorganization of the clustered Hox genes in embryonic stem cells induced by retinoic acid J. Biol. Chem. 2011
9697850 Initiation of rhombomeric Hoxb4 expression requires induction by somites and a retinoid pathway Neuron 1998
15634700 Direct crossregulation between retinoic acid receptor {beta} and Hox genes during hindbrain segmentation Development 2005
25101834 KDM6 demethylase independent loss of histone H3 lysine 27 trimethylation during early embryonic development PLoS Genet. 2014
10373014 RARbeta mediates the response of Hoxd4 and Hoxb4 to exogenous retinoic acid Dev. Dyn. 1999
23955559 Saltatory remodeling of Hox chromatin in response to rostrocaudal patterning signals Nat. Neurosci. 2013
Orthologous Events