XB-ART-43205J Biol Chem June 17, 2011; 286 (24): 21853-64.
WD repeat-containing protein 5, a ubiquitously expressed histone methyltransferase adaptor protein, regulates smooth muscle cell-selective gene activation through interaction with pituitary homeobox 2.
WD repeat-containing protein 5 (WDR5) is a common component of mammalian mixed lineage leukemia methyltransferase family members and is important for histone H3 lysine 4 methylation (H3K4me), which has been implicated in control of activation of cell lineage genes during embryogenesis. However, WDR5 has not been considered to play a specific regulatory role in epigenetic programming of cell lineage because it is ubiquitously expressed. Previous work from our laboratory showed the appearance of histone H3K4me within smooth muscle cell (SMC)-marker gene promoters during the early stages of development of SMC from multipotential embryonic cells but did not elucidate the underlying mechanisms that mediate SMC-specific and locus-selective H3K4me. Results presented herein show that knockdown of WDR5 significantly decreased SMC-marker gene expression in cultured SMC differentiation systems and in Xenopus laevis embryos in vivo. In addition, we showed that WDR5 complexes within SMC progenitor cells contained H3K4 methyltransferase enzymatic activity and that knockdown of WDR5 selectively decreased H3K4me1 and H3K4me3 enrichment within SMC-marker gene promoter loci. Moreover, we present evidence that it is recruited to these gene promoter loci through interaction with a SMC-selective pituitary homeobox 2 (Pitx2). Taken together, studies provide evidence for a novel mechanism for epigenetic control of SMC-marker gene expression during development through interaction of WDR5, homeodomain proteins, and chromatin remodeling enzymes.
PubMed ID: 21531708
PMC ID: PMC3122240
Article link: J Biol Chem
Species referenced: Xenopus
Genes referenced: acta2 actl6a ash2l casp3.2 gan h3-3a klf4 myh11 rbbp5 srf tagln tagln2 tbx2 tuba4b wdr5
Antibodies: Acta2 Ab1
Morpholinos: wdr5 MO1 wdr5 MO3
Article Images: [+] show captions
|FIGURE 3. Morpholino-mediated knockdown of WDR5 in X. laevis significantly decreased SMC-marker gene expression in vivo. In situ hybridization analyses of SM -actin (A),SM22 (E), andSM-MHC(I) mRNA expression in stage 42 X. laevis embryos injected with either control morpholinos or WDR5 morpholinos at the two-cell stage. The location of visceral muscle and the dorsal aorta are indicated with arrows, whereas arrowheads highlight embryonic regions with either reduced visceral muscle (VM) cells or dorsal aortic (DA) cells expressing SMC-marker genes. B,D, F,H, J, and L represent higher magnifications of panels A, C, E, G, I, and K, respectively. This research was originally published in The Journal of Biological Chemistry. Gan et al “WD repeat-containing protein 5, a ubiquitously expressed histone methyltransferase adaptor protein, regulates smooth muscle cell-selective gene activation through interaction with pituitary homeobox 2.” June 17, 2011; 286 (24): 21853-21864. © The American Society for Biochemistry and Molecular Biology. Reproduced with permission.|
References [+] :
Barillot, Induction and modulation of smooth muscle differentiation in Xenopus embryonic cells. 2008, Pubmed, Xenbase