Brg1 Enables Rapid Growth of the Early Embryo by Suppressing Genes That Regulate Apoptosis and Cell Growth Arrest

Abstract

SWI/SNF (switching/sucrose nonfermenting)-dependent chromatin remodeling establishes coordinated gene expression programs during development, yet important functional details remain to be elucidated. We show that the Brg1 (Brahma-related gene 1; Smarca4) ATPase is globally expressed at high levels during postimplantation development and its conditional ablation, beginning at gastrulation, results in increased apoptosis, growth retardation, and, ultimately, embryonic death. Global gene expression analysis revealed that genes upregulated in Rosa26CreERT2; Brg1^flox/flox embryos (here referred to as Brg1^d/d embryos to describe embryos with deletion of the Brg1^flox/flox alleles) negatively regulate cell cycle progression and cell growth. In addition, the p53 (Trp53) protein, which is virtually undetectable in early wild-type embryos, accumulated in the Brg1^d/d embryos and activated the p53-dependent pathways. Using P19 cells, we show that Brg1 and CHD4 (chromodomain helicase DNA binding protein 4) coordinate to control target gene expression. Both proteins physically interact and show a substantial overlap of binding sites at chromatin-accessible regions adjacent to genes differentially expressed in the Brg1^d/d embryos. Specifically, Brg1 deficiency results in reduced levels of the repressive histone H3 lysine K27 trimethylation (H3K27me3) histone mark and an increase in the amount of open chromatin at the regulatory region of the p53 and p21 (Cdkn1a) genes. These results provide insights into the mechanisms by which Brg1 functions, which is in part via the p53 program, to constrain gene expression and facilitate rapid embryonic growth.

ACKNOWLEDGMENTS

We thank Harriet Kinyamu, Steven Akiyama, Mitch Eddy, and Jackson Hoffman for critical review of the manuscript. We gratefully thank the Histology and Immunohistochemistry Core Facility, including Ronald Herbert and Natasha Clayton; Eli Ney of the Imaging Core Facility; the Molecular Genomics Core Facility, including Kevin Gerrish; and the Flow Cytometry Facility. We thank Katrina Loper for excellent service in the maintenance of the mouse colonies.

The Intramural Research Program of the NIH, National Institute of Environmental Health Sciences, supported this research (project Z01 ES071006-15 to T.K.A.).

We specify no conflict of interest.