Reactome: A Curated Pathway Database

Retinoic acid activates Hoxd4 chromatin

Stable Identifier
Reaction [BlackBoxEvent]
Mus musculus

Retinoic acid activates the Hoxd4 gene in rhombomere 7 (r7) of embryos by binding Rarb (Folberg et al. 1999, Serpente et al. 2005), Rara, or Rarg (Wendling et al. 2001) in Rar:Rxr receptor dimers bound to a retinoic acid response element (RARE) in the 5' flanking region of the gene (Popperl and Featherstone 1993, Folberg et al. 1997, Zhang et al. 1997, Zhang et al. 2000, Wendling et al. 2001, Nolte et al. 2003). Ligand binding by retinoic acid receptors causes dismissal of corepressors such as Ncor1 and recruitment of coactivators such as Ncoa3 (Horlein et al. 1995, inferred from Hoxa1 in Gillespie and Gudas 2007, Kashyap and Gudas 2010). Pax6 binds near the RARE and is required for maximal activation (Nolte et al. 2006).
Activation of chromatin at Hoxd4 is accompanied by loss of methylation at lysine-27 (H3K27me3) and gain of H3K4me3 (Rastegar et al. 2012, Williamson et al. 2012, Mazzoni et al. 2013). The Mll2 complex methylates H3K4 at Hoxd4 in fibroblasts (Wang et al. 2009). In human cells the histone demethylase KDM6A (UTX) binds HOXD4 and may participate in demethylating H3K27me3. Other factors may also be involved in histone demethylation. Polycomb repressive complex 2 (PRC2), which binds H3K27me3, and Pcgf2 (Mel18) also dissociate (Kobrossy et al. 2006, Mazzoni et al. 2013). YY1, however, remains associated even after treatment with retinoic acid (Kobrossy et al. 2006). After activation by retinoic acid, Hoxd4 maintains its own expression by binding and activating its own promoter (Kobrossy et al. 2006).

Literature References
PubMed ID Title Journal Year
15340071 Sequential histone modifications at Hoxd4 regulatory regions distinguish anterior from posterior embryonic compartments Mol. Cell. Biol. 2004
7566114 Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor Nature 1995
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
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
12591602 The role of a retinoic acid response element in establishing the anterior neural expression border of Hoxd4 transgenes Mech. Dev. 2003
10940626 Murine hoxd4 expression in the CNS requires multiple elements including a retinoic acid response element Mech. Dev. 2000
10373014 RARbeta mediates the response of Hoxd4 and Hoxb4 to exogenous retinoic acid Dev. Dyn. 1999
22872084 Anterior-posterior differences in HoxD chromatin topology in limb development Development 2012
20231276 Epigenetic regulatory mechanisms distinguish retinoic acid-mediated transcriptional responses in stem cells and fibroblasts J. Biol. Chem. 2010
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16757478 Interplay between chromatin and trans-acting factors regulating the Hoxd4 promoter during neural differentiation J. Biol. Chem. 2006
15634700 Direct crossregulation between retinoic acid receptor {beta} and Hox genes during hindbrain segmentation Development 2005
9347914 Elements both 5' and 3' to the murine Hoxd4 gene establish anterior borders of expression in mesoderm and neurectoderm Mech. Dev. 1997
11493525 Roles of retinoic acid receptors in early embryonic morphogenesis and hindbrain patterning Development 2001
8093325 Identification of a retinoic acid response element upstream of the murine Hox-4.2 gene Mol. Cell. Biol. 1993
23955559 Saltatory remodeling of Hox chromatin in response to rostrocaudal patterning signals Nat. Neurosci. 2013
9360992 Characterization and retinoic acid responsiveness of the murine Hoxd4 transcription unit J. Biol. Chem. 1997
Orthologous Events