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BRG1 deletion de‐represses p53 pathways inducing cell cycle inhibition and apoptosis during peri‐gastrulation (541.10)
Author(s) -
Singh Ajeet,
Boyle Michael C,
Rubino Mark,
Tandon Arpit,
Shah Ruchir,
Archer Trevor
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.541.10
Subject(s) - chromatin remodeling , biology , microbiology and biotechnology , gastrulation , carcinogenesis , embryonic stem cell , swi/snf , chromatin , cell cycle , cancer research , embryogenesis , embryo , gene , genetics
BRG1, a catalytic subunit of the SWI/SNF ATPase chromatin‐remodeling complex, plays a vital role in gene regulation and tumorigenesis. Germline SWI/SNF function loss results in early embryonic lethality at approximately E3.5 in the mouse. BRG1 necessity during development beyond the pre‐implantation stage, however, has not been defined. The myriad temporal genomic changes during development require chromatin remodeling to facilitate differential gene expression. We hypothesized that BRG1 deficiency during post‐implantation development will cause gastrulation failure. Using a tamoxifen inducible conditional mouse model, we show that BRG1 ablation beginning at gastrulation results in arrested growth and early embryonic death. Mutant embryos failed to grow; histologic analysis revealed several developmental defects such as lack of normal cardiac structure and disrupted neural fold architecture. Immunohistochemistry analysis revealed aberrant expression of cell cycle and apoptosis marker proteins in BRG1 mutants. Microarray analysis revealed BRG1 ablation increased expression of cell cycle regulators, particularly within the p53 pathway. Co‐IP analyses reveal BRG1 interacts with CHD4 to suppress p53 pathways in P19 cells. These results suggest BRG1 plays a critical role in genomic surveillance essential for cell survival after the pre‐implantation period for normal cellular survival, proliferation and differentiation. Grant Funding Source : Z01 ES071006‐13