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Proc Natl Acad Sci U S A. 2016 Mar 29;113(13):3545-50. doi: 10.1073/pnas.1519994113. Epub 2016 Mar 11.

Sp5 and Sp8 recruit β-catenin and Tcf1-Lef1 to select enhancers to activate Wnt target gene transcription.

Author information

1
Cancer and Developmental Biology Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD;
2
Center for Cancer Research Collaborative Bioinformatics Resource, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD 21702.
3
Cancer and Developmental Biology Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD; yamagute@mail.nih.gov.

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.

KEYWORDS:

Sp5/Sp8; Tcf/Lef; Wnt; stem cells; transcription

PMID:
26969725
PMCID:
PMC4822596
DOI:
10.1073/pnas.1519994113
[Indexed for MEDLINE]
Free PMC Article

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