title: 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.
abstract: 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.
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Gan
authors.forename: Pierre
authors.initials: P
authors.lastname: Thiébaud
authors.forename: Nadine
authors.initials: N
authors.lastname: Thézé
authors.forename: Li
authors.initials: L
authors.lastname: Jin
authors.forename: Guofeng
authors.initials: G
authors.lastname: Xu
authors.forename: Patrick
authors.initials: P
authors.lastname: Grant
authors.forename: Gary K
authors.initials: GK
authors.lastname: Owens
mesh_terms: D000818:Animals; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D018507:Gene Expression Regulation, Developmental; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry*; D018398:Homeodomain Proteins / Q000737:chemistry / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence / Q000379:methods; D009130:Muscle, Smooth / Q000378:metabolism*; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism / Q000502:physiology*; D034741:RNA, Small Interfering / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014982:Xenopus laevis; D000097577:Homeobox Protein PITX2
chemical_list: D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2; C443118:Wdr5 protein, mouse