Reactome: A Curated Pathway Database

Retinoic acid activates Hoxa1 chromatin

Stable Identifier
R-MMU-5617990
Type
Reaction [BlackBoxEvent]
Species
Mus musculus
Compartment
Summation

Experiments in mouse embryos (Frasch et al. 1995, Dupe et al. 1997, Paschaki et al. 2013), embryonal carcinoma cell lines (Langston and Gudas 1992, Langston et al. 1997, Gillespie and Gudas 2007, Kashyap and Gudas 2010), and embryonic stem cells (Lee et al. 2007, Chen and Reese 2011, Kashyap et al. 2011, Mazzoni et al. 2013) indicate retinoic acid binds the Rara or Rarg receptor in a RAR:RXR dimer bound to the 3' region of Hoxa1 and causes activation of Hoxa1 expression. Hoxa1 in turn binds and activates the promoter of the Raldh2 gene to create a feedback loop that maintains retinoic acid synthesis (Vitobella et al. 2011).
Observations in embryonic carcinoma cells indicate the mechanism of activation of retinoic acid receptors proceeds through ligand-dependent release (dismissal) of corepressors such as Ncor1, Ajuba, and Hdac3 followed by recruitment of coactivators such as Ncoa3 and Ep300 (p300) (Horlein et al. 1995, Perissi et al. 2004, Gillespie and Gudas 2007, Hou et al. 2010, Kashyap and Gudas 2010, Bajpe et al. 2013). During activation by retinoic acid chromatin in the region of the Hoxa1 gene is modified from a bivalent state to an active conformation by losing methylation at lysine-27 of histone H3 and associated polycomb repressive proteins (Gillespie and Gudas 2007, Lee et al. 2007, Kashyap and Gudas 2010, Kashyap et al. 2011, Mazzoni et al. 2013). Though experiments with cultured human cells show KDM6A (UTX) and KDM6B (JMJD3) actively demethylate H3K27me3, mouse embryos that lack both Kdm6a and Kdm6b still show loss of H3K27me3 during activation of Hox genes in embryos (Shpargel et al. 2014), therefore other factors may also participate in loss of H3K27me3. A loss of histone deacetylases (HDAC1,2,3) and a gain of histone acetylation (Lee et al. 2007, Urvalek and Gudas 2014) and H3K4me3 (Kashyap et al. 2011) is also associated with activation of Hoxa1 in embryonic stem cells. The Mll2 complex acetylates H3K4 at Hoxa1 in fibroblasts (Wang et al. 2009).
Expression of Hoxa1 occurs in the neural tube, adjacent mesenchyme, paraxial mesoderm, somites, and gut epithelium from the the border between rhombomeres 3 and 4 (r3/r4) to the caudal-most region of the embryo (Baron et al. 1987, Sundin et al, 1990, Murphy and Hill 1991, Godwin et al. 1998, reviewed in Alexander et al. 2009). Prior to formation of rhombomeres, Hoxa1 is expressed weakly in the region of the embryo that will become rhombomere 2 (r2) and strongly in the region that will become r3-7. Expression is transient and ceases by the time rhombomeres form. (Rhombomeres are transiently formed segments in the neural tube that will eventually form the hindbrain.)

Literature References
PubMed ID Title Journal Year
20133701 LIM protein Ajuba functions as a nuclear receptor corepressor and negatively regulates retinoic acid signaling Proc. Natl. Acad. Sci. U.S.A. 2010
1693558 Region-specific expression in early chick and mouse embryos of Ghox-lab and Hox 1.6, vertebrate homeobox-containing genes related to Drosophila labial Development 1990
17525233 High histone acetylation and decreased polycomb repressive complex 2 member levels regulate gene specific transcriptional changes during early embryonic stem cell differentiation induced by retinoic acid Stem Cells 2007
9053316 In vivo functional analysis of the Hoxa-1 3' retinoic acid response element (3'RARE) Development 1997
20231276 Epigenetic regulatory mechanisms distinguish retinoic acid-mediated transcriptional responses in stem cells and fibroblasts J. Biol. Chem. 2010
19575673 Hox genes and segmentation of the hindbrain and axial skeleton Annu. Rev. Cell Dev. Biol. 2009
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
21087926 Epigenomic reorganization of the clustered Hox genes in embryonic stem cells induced by retinoic acid J. Biol. Chem. 2011
1673098 Expression of the mouse labial-like homeobox-containing genes, Hox 2.9 and Hox 1.6, during segmentation of the hindbrain Development 1991
20836077 Retinoids regulate stem cell differentiation J. Cell. Physiol. 2011
14980219 A corepressor/coactivator exchange complex required for transcriptional activation by nuclear receptors and other regulated transcription factors Cell 2004
25101834 KDM6 demethylase independent loss of histone H3 lysine 27 trimethylation during early embryonic development PLoS Genet. 2014
24821725 Retinoic acid and histone deacetylases regulate epigenetic changes in embryonic stem cells J. Biol. Chem. 2014
17875646 Retinoic acid receptor isotype specificity in F9 teratocarcinoma stem cells results from the differential recruitment of coregulators to retinoic response elements J. Biol. Chem. 2007
21618588 The retinol signaling pathway in mouse pluripotent P19 cells J. Cell. Biochem. 2011
7743939 Evolutionary-conserved enhancers direct region-specific expression of the murine Hoxa-1 and Hoxa-2 loci in both mice and Drosophila Development 1995
23638021 Transcriptomic analysis of murine embryos lacking endogenous retinoic acid signaling PLoS ONE 2013
21497760 Hox and Pbx factors control retinoic acid synthesis during hindbrain segmentation Dev. Cell 2011
1360810 Identification of a retinoic acid responsive enhancer 3' of the murine homeobox gene Hox-1.6 Mech. Dev. 1992
9789037 Detection of targeted GFP-Hox gene fusions during mouse embryogenesis Proc. Natl. Acad. Sci. U.S.A. 1998
2891503 Hox-1.6: a mouse homeo-box-containing gene member of the Hox-1 complex EMBO J. 1987
8999919 Retinoic acid-responsive enhancers located 3' of the Hox A and Hox B homeobox gene clusters. Functional analysis J. Biol. Chem. 1997
23955559 Saltatory remodeling of Hox chromatin in response to rostrocaudal patterning signals Nat. Neurosci. 2013
Participants
Orthologous Events