The H2A.Z histone variant integrates Wnt signaling in intestinal epithelial homeostasis

Jérémie Rispal,Martine Chevillard-Briet,Didier Trouche,Lucie Baron,Jean-François Beaulieu,Fabrice Escaffit

doi:10.1038/s41467-019-09899-z

Abstract

The Tip60/p400 chromatin-modifying complex, which is involved in the incorporation and post-translational modification of the H2A.Z histone variant, regulates cell proliferation and important signaling pathways, such as Wnt. Here, we study the involvement of H2A.Z in intestinal epithelial homeostasis, which is dependent on the finely-tuned equilibrium between stem cells renewal and differentiation, under the control of such pathway. We use cell models and inducible knock-out mice to study the impact of H2A.Z depletion on intestinal homeostasis. We show that H2A.Z is essential for the proliferation of human cancer and normal intestinal crypt cells and negatively controls the expression of a subset of differentiation markers, in cultured cells and mice. H2A.Z impairs the recruitment of the intestine-specific transcription factor CDX2 to chromatin, is itself a target of the Wnt pathway and thus, acts as an integrator for Wnt signaling in the control of intestinal epithelial cell fate and homeostasis.

Highlights

The Tip60/p400 chromatin-modifying complex, which is involved in the incorporation and post-translational modification of the H2A.Z histone variant, regulates cell proliferation and important signaling pathways, such as Wnt
We demonstrated that these effects are dependent on the Wnt pathway, a well-known signaling pathway involved in cancer, and critical for the development and homeostasis of the normal intestine
Taken together, we demonstrate an epistatic relationship between histone variant incorporation and binding of the crucial transcription factor CDX2, demonstrating that the H2A.Z histone variant exerts a central role in tissue homeostasis by integrating key signaling by the Wnt pathway

Summary

Introduction

The Tip60/p400 chromatin-modifying complex, which is involved in the incorporation and post-translational modification of the H2A.Z histone variant, regulates cell proliferation and important signaling pathways, such as Wnt. Here, we study the involvement of H2A.Z in intestinal epithelial homeostasis, which is dependent on the finely-tuned equilibrium between stem cells renewal and differentiation, under the control of such pathway. We recently showed[1] that the Tip60/p400 enzymatic complex plays a critical role in colon cancer, regulating susceptibility to chemically-induced pre-neoplastic lesions and adenomas We demonstrated that these effects are dependent on the Wnt pathway, a well-known signaling pathway involved in cancer, and critical for the development and homeostasis of the normal intestine. While histone acetylation by Tip[60] is globally associated with the activation of transcription[8], the incorporation of H2A.Z can differently affect gene expression depending on the gene, chromatin context or post-translational modification of H2A.Z itself[3,5,9,10,11]

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