The WNT target SP5 negatively regulates WNT transcriptional programs in human pluripotent stem cells

Ian J Huggins,Tomas Bos,Karl Willert,Angeline Puranen,David Brafman,Charlotte Rossdam,Terry Gaasterland,Christina Jessen,Brianna Lonquich,Jenna Richter,Olivia Gaylord

doi:10.1038/s41467-017-01203-1

Abstract

The WNT/β-catenin signaling pathway is a prominent player in many developmental processes, including gastrulation, anterior–posterior axis specification, organ and tissue development, and homeostasis. Here, we use human pluripotent stem cells (hPSCs) to study the dynamics of the transcriptional response to exogenous activation of the WNT pathway. We describe a mechanism involving the WNT target gene SP5 that leads to termination of the transcriptional program initiated by WNT signaling. Integration of gene expression profiles of wild-type and SP5 mutant cells with genome-wide SP5 binding events reveals that SP5 acts to diminish expression of genes previously activated by the WNT pathway. Furthermore, we show that activation of SP5 by WNT signaling is most robust in cells with developmental potential, such as stem cells. These findings indicate a mechanism by which the developmental WNT signaling pathway reins in expression of transcriptional programs.

Highlights

The WNT/β-catenin signaling pathway is a prominent player in many developmental processes, including gastrulation, anterior–posterior axis specification, organ and tissue development, and homeostasis
To study the effects of WNT signaling in human pluripotent stem cells (hPSCs), we analyzed the transcriptomes of cells treated for 12, 24, and 48 h with Wnt3a by high-throughput RNA sequencing (RNA-Seq)
While WNT/β-catenin signaling has known mechanisms to antagonize components of the pathway, including WNT receptors and the WNT protein itself, and thereby desensitize cells to subsequent WNT signals, little was known about how key target genes were subsequently downregulated

Summary

Introduction

The WNT/β-catenin signaling pathway is a prominent player in many developmental processes, including gastrulation, anterior–posterior axis specification, organ and tissue development, and homeostasis. The WNT/β-catenin signaling pathway (commonly referred to as the canonical WNT pathway), which is highly conserved across all metazoan life forms, is essential for embryonic development and, later in life, for adult tissue homeostasis and regeneration. Deregulation of this pathway causes severe congenital defects, underlies multiple diseases and disorders, and frequently drives oncogenic transformation The SP5 transcription factor emerged as a critical downstream WNT target that acts to rein in expression of a large swath of genes previously activated by the WNT signal These findings suggest a mechanism by which a developmental signaling pathway acts to dynamically regulate gene expression

Methods

Results

Conclusion