title: Sp5 and Sp8 recruit β-catenin and Tcf1-Lef1 to select enhancers to activate Wnt target gene transcription.
abstract: The ancient, highly conserved, Wnt signaling pathway regulates cell fate in all metazoans. We have previously shown that combined null mutations of the specificity protein (Sp) 1/Klf-like zinc-finger transcription factors Sp5 and Sp8 (i.e., Sp5/8) result in an embryonic phenotype identical to that observed when core components of the Wnt/β-catenin pathway are mutated; however, their role in Wnt signal transduction is unknown. Here, we show in mouse embryos and differentiating embryonic stem cells that Sp5/8 are gene-specific transcriptional coactivators in the Wnt/β-catenin pathway. Sp5/8 bind directly to GC boxes in Wnt target gene enhancers and to adjacent, or distally positioned, chromatin-bound T-cell factor (Tcf) 1/lymphoid enhancer factor (Lef) 1 to facilitate recruitment of β-catenin to target gene enhancers. Because Sp5 is itself directly activated by Wnt signals, we propose that Sp5 is a Wnt/β-catenin pathway-specific transcript on factor that functions in a feed-forward loop to robustly activate select Wnt target genes.
authors.affiliation: Cancer and Developmental Biology Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD;
authors.forename: Mark W
authors.initials: MW
authors.lastname: Kennedy
authors.affiliation: Cancer and Developmental Biology Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD;
authors.forename: Ravindra B
authors.initials: RB
authors.lastname: Chalamalasetty
authors.affiliation: Cancer and Developmental Biology Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD;
authors.forename: Sara
authors.initials: S
authors.lastname: Thomas
authors.affiliation: Cancer and Developmental Biology Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD;
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Garriock
authors.affiliation: Center for Cancer Research Collaborative Bioinformatics Resource, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD 21702.
authors.forename: Parthav
authors.initials: P
authors.lastname: Jailwala
authors.affiliation: Cancer and Developmental Biology Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD; yamagute@mail.nih.gov.
authors.forename: Terry P
authors.initials: TP
authors.lastname: Yamaguchi
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D047108:Embryonic Development / Q000235:genetics; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D005260:Female; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism*; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011247:Pregnancy; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D060449:Wnt Signaling Pathway / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C495267:CTNNB1 protein, mouse; D004268:DNA-Binding Proteins; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; C497574:Lef1 protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; C417217:Sp5 protein, mouse; C490035:Sp8 protein, mouse; D014157:Transcription Factors; D051176:beta Catenin
keywords: Sp5/Sp8; Tcf/Lef; Wnt; stem cells; transcription