Brg1 plays an essential role in development and homeostasis of the duodenum through regulation of Notch signaling.

Yutaka Takada,Tsutomu Chiba,Akihisa Fukuda,Hiroshi Seno

doi:10.1242/dev.141549

Abstract

Brg1, a core subunit of the SWI/SNF chromatin remodeling complex, is essential for development and homeostasis of various organs. However, the functional role of Brg1 in intestinal development and homeostasis, and the underlying molecular mechanism, remain unknown. We found that deletion of Brg1 in the mouse intestine resulted in growth impairment and early death associated with abnormal crypt-villous formation, skewed differentiation into secretory lineage cells, markedly increased apoptosis, and stem cell loss in the duodenum. Furthermore, we found that the Notch signaling pathway was dramatically downregulated in Brg1-deficient duodenum. Remarkably, overexpression of the Notch1 intercellular domain (ICD) partially reversed the prognosis of intestinal Brg1 mutant mice. Notch1 ICD overexpression rescued morphogenesis, prevented over-differentiation into secretory lineage cells, and restored apoptosis to normal levels in Brg1-deficient duodenum, although stem cell loss was not rescued. Our data demonstrate that Brg1 plays an essential role in development and homeostasis, including morphogenesis, stem cell differentiation and cell survival in the duodenum. Mechanistically, the rescue of the intestinal Brg1 mutant phenotype by overexpression of the Notch1 ICD indicates that Notch signaling is a key downstream target that mediates the effects of Brg1.

Highlights

Tissue development and homeostasis are governed by activation or inactivation of multiple genes
In this study, intestinal Brg1 mutant mice presented with early postnatal death associated with impaired crypt-villous formation, skewed differentiation into secretary lineage, markedly increased apoptosis and stem cell loss in the duodenum
Notch1 intercellular domain (ICD) overexpression rescued impaired morphogenesis, over-differentiation into secretary lineage and elevated apoptosis in the absence of Brg1, demonstrating that Brg1 plays a pivotal role for intestinal development and homeostasis via a Notch signaling-dependent mechanism

Summary

Introduction

Tissue development and homeostasis are governed by activation or inactivation of multiple genes. Because chromatin is highly compacted, it must undergo structural changes to allow transcription factors to interact with nucleosomes and access binding sites on their target genes. ATP-dependent chromatin remodeling complexes alter local chromatin structure using energy from ATP hydrolysis. These structural alterations increase or decrease the accessibility of transcriptional factors and thereby activate or repress the expression of specific genes (Hargreaves and Crabtree, 2011; Helming et al, 2014; Martens and Winston, 2003; Wilson and Roberts, 2011). SWI/SNF (Switch/sucrose non-fermentable) complexes are evolutionarily conserved ATP-dependent chromatin remodeling complexes consisting of multiple protein subunits.

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