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

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.

Chromatin Dynamics in Intestinal Epithelial Homeostasis: A Paradigm of Cell Fate Determination versus Cell Plasticity

“…However, it remains to be seen whether p400 complex is recruited by transcription factors of the Wnt pathway (β-Catenin or TCF4) or not. Moreover, SCRAP complex, another INO80/SWR complex, exerts a major role in intestinal homeostasis through H2A.Z histone variant incorporation [37], itself involved in intestinal cell proliferation [36,37]. Thus, it would be interesting to study if p400 complex regulates Wnt pathway activity and proliferation in a H2A.Z-dependent or -independent way.…”

“…H2A.Z plays an essential role in the maintenance of intestinal epithelium integrity and its constant renewal. Rispal et al demonstrated that H2A.Z.1 (the most studied isoform) is important for the proliferation of intestinal cells [ 36 ]. Zhao and collaborators showed that deletion of both H2A.Z isoforms (H2A.Z.1 and H2A.Z.2) leads to severe morphological changes of the intestinal epithelium, resulting in important weight loss in mice.…”

“…H2A.Z is also important for the control of intestinal differentiation [ 36 ]. Rispal et al demonstrated the inhibitory role of H2A.Z.1 on the expression of differentiation genes specific for enterocytes ( SI, LPH ) and for goblet cells ( MUC2, MUC4 ) in cellulo and in vivo .…”

Non-redundant functions of H2A.Z.1 and H2A.Z.2 in chromosome segregation and cell cycle progression

“…Several studies have linked H2A.Z to transcription regulation [13][14][15][16][17]28 ; whether it promotes or represses gene expression still remains controversial. These differences Using STRING analyses, we identified a highly significant protein-protein interaction (PPI) enrichment (p = 10 -16 ) in the downregulated genes of H2A.Z.1-depleted cellsthis is the only group that showed a significant PPI enrichment.…”

“…Several studies have highlighted the importance of H2A.Z in transcription regulation [13][14][15][16][17] . However, whether H2A.Z promotes or represses transcription appears to depend on the gene, chromatin complex, and post-translational modifications of H2A.Z itself 18 .…”