Maternal BRG1 regulates zygotic genome activation in the mouse

Genes and Development - Tập 20 Số 13 - Trang 1744-1754 - 2006
Scott J. Bultman1, Thomas C. Gebuhr2,3, Hua Pan4, Petr Svoboda5,6, Richard M. Schultz4, Terry Magnuson7
1Department of Genetics and The Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
2Novartis, USA
3University of North Carolina
4#N# * University of Pennsylvania.
5Novartis
6University of Pennsylvania,
7Lineberger Comprehensive Cancer Center

Tóm tắt

Zygotic genome activation (ZGA) is a nuclear reprogramming event that transforms the genome from transcriptional quiescence at fertilization to robust transcriptional activity shortly thereafter. The ensuing gene expression profile in the cleavage-stage embryo establishes totipotency and is required for further development. Although little is known about the molecular basis of ZGA, oocyte-derived mRNAs and proteins that alter chromatin structure are likely crucial. To test this hypothesis, we generated a maternal-effect mutation of Brg1, which encodes a catalytic subunit of SWI/SNF-related complexes, utilizing Cre-loxP gene targeting. In conditional-mutant females, BRG1-depleted oocytes completed meiosis and were fertilized. However, embryos conceived from BRG1-depleted eggs exhibited a ZGA phenotype including two-cell arrest and reduced transcription for ∼30% of expressed genes. Genes involved in transcription, RNA processing, and cell cycle regulation were particularly affected. The early embryonic arrest is not a consequence of a defective oocyte because depleting maternal BRG1 after oocyte development is complete by RNA interference (RNAi) also resulted in two-cell arrest. To our knowledge, Brg1 is the first gene required for ZGA in mammals. Depletion of maternal BRG1 did not affect global levels of histone acetylation, whereas dimethyl-H3K4 levels were reduced. These data provide a framework for understanding the mechanism of ZGA.

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