Reactome: A Curated Pathway Database

Retinoic acid activates Hoxb1 chromatin

Stable Identifier
Reaction [BlackBoxEvent]
Mus musculus

In mouse embryos (Marshall et al. 1994, Studer et al. 1994, Wendling et al. 2001, Huang et al. 2002, Roelen et al. 2002), carcinoma cell lines (Ogura and Evans 1995, Chiba et al. 1997, Langston et al. 1997), and embryonic stem cells (Kashyap et al. 2011, Mazzoni et al. 2013) retinoic acid activates Hoxb1 by binding receptors, Rara or Rarg (in embryos in Wendling et al. 2001, in embryonal carcinoma cells in Chiba et al. 1997), at retinoic acid response elements (RAREs) located 3' to the Hoxb1 gene (Marshall et al. 1994, Ogura and Evans 1995, Langston et al. 1997, Huang et al. 2002) and 5' to the Hoxb1 gene (Ogura et al. 1995), causing dismissal of corepressors, recruitment of coactivators, and alteration of chromatin to an active conformation (inferred from Hoxa1, Gillespie and Gudas 2007, Kashyap and Gudas 2010).
In human cells, KDM6A (UTX) binds the HOXB1 gene upon retinoic acid treatment and may demethylate trimethylated lysine-27 of histone H3 (H3K27me3). Demethylation of H3K27me3 at the Hoxb cluster is similarly observed in mouse embryonic stem cells treated with retinoic acid (Kashyap et al. 2011, Mazzoni et al. 2013). Other factors may also cause demethylation of H3K27me3 (Shpargel et al. 2014). Polycomb repressive complex 2 (PRC2), which binds H3K27me3, is also lost during activation (Mazzoni et al. 2013). In human cells KDM6A associates with the methyltransferases KMT2C,D (MLL2,3) which may participate in methylating histone H3 at lysine-4 (H3K4me3), an activating chromatin modification. Gain of H3K4me3 is also observed in mouse embryonic stem cells (Kashyap et al. 2011). The Mll2 complex methylates H3K4 at Hoxb1 in mouse fibroblasts (Wang et al. 2009). In mouse embryos Hoxa1 synergizes with retinoic acid to activate Hoxb1 (Studer et al. 1998, Gavalas et al. 1998). After activation by retinoic acid, Hoxb1 maintains its own expression by forming a ternary Hoxb1:Pknox1:Pbx1 (Hoxb1:Prep1:Pbx1) complex at elements in its own promoter and activating expression (Ogura and Evans 1995, Di Rocco et al. 1997, Ferretti et al. 2005).
Hoxb1 is expressed in mesoderm and neurectoderm of primitive streak stage embryos and then becomes restricted to rhombomeres of the hindbrain (Murphy et al. 1989, Wilkinson et al. 1989, Bogue et al. 1996). Before rhombomere formation Hoxb1 is initially expressed weakly in the region that will become rhombomere 2 (r2) and strongly in the region that becomes r3-7. After rhombomere formation Hoxb1 becomes restricted to r4 and is also observed in caudal mesoderm (Murphy et al. 1989, Arenkiel et al. 2003). Hoxb1 activates expression of Egr2 (Krox20, Wassef et al. 2008), a transcription factor that subsequently activates Hoxa2, Hoxb2, and Hoxb3 but represses Hoxb1.

Literature References
PubMed ID Title Journal Year
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
16166636 Hoxb1 enhancer and control of rhombomere 4 expression: complex interplay between PREP1-PBX1-HOXB1 binding sites Mol. Cell. Biol. 2005
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
9154799 Distinct retinoid X receptor-retinoic acid receptor heterodimers are differentially involved in the control of expression of retinoid target genes in F9 embryonal carcinoma cells Mol. Cell. Biol. 1997
7831297 Evidence for two distinct retinoic acid response pathways for HOXB1 gene regulation Proc. Natl. Acad. Sci. U.S.A. 1995
7831296 A retinoic acid-triggered cascade of HOXB1 gene activation Proc. Natl. Acad. Sci. U.S.A. 1995
8703472 Expression of Hoxb genes in the developing mouse foregut and lung Am. J. Respir. Cell Mol. Biol. 1996
12815623 Hoxb1 neural crest preferentially form glia of the PNS Dev. Dyn. 2003
2571936 Segmental expression of Hox-2 homoeobox-containing genes in the developing mouse hindbrain Nature 1989
7916164 Role of a conserved retinoic acid response element in rhombomere restriction of Hoxb-1 Science 1994
20231276 Epigenetic regulatory mechanisms distinguish retinoic acid-mediated transcriptional responses in stem cells and fibroblasts J. Biol. Chem. 2010
7914354 A conserved retinoic acid response element required for early expression of the homeobox gene Hoxb-1 Nature 1994
9218805 Functional dissection of a transcriptionally active, target-specific Hox-Pbx complex EMBO J. 1997
9463349 Genetic interactions between Hoxa1 and Hoxb1 reveal new roles in regulation of early hindbrain patterning Development 1998
12385756 Hox cluster polarity in early transcriptional availability: a high order regulatory level of clustered Hox genes in the mouse Mech. Dev. 2002
11891985 Analysis of two distinct retinoic acid response elements in the homeobox gene Hoxb1 in transgenic mice Dev. Dyn. 2002
8999919 Retinoic acid-responsive enhancers located 3' of the Hox A and Hox B homeobox gene clusters. Functional analysis J. Biol. Chem. 1997
2571087 Segment-specific expression of a homoeobox-containing gene in the mouse hindbrain Nature 1989
18787068 Rostral hindbrain patterning involves the direct activation of a Krox20 transcriptional enhancer by Hox/Pbx and Meis factors Development 2008
11493525 Roles of retinoic acid receptors in early embryonic morphogenesis and hindbrain patterning Development 2001
23955559 Saltatory remodeling of Hox chromatin in response to rostrocaudal patterning signals Nat. Neurosci. 2013
9463359 Hoxa1 and Hoxb1 synergize in patterning the hindbrain, cranial nerves and second pharyngeal arch Development 1998
Orthologous Events