Maternal BRG1 regulates zygotic genome activation in the mouse.
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 approximately 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.
Bultman
Scott J
SJ
Department of Genetics and The Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, North Carolina 27599, USA. scott_bultman@med.unc.edu
Gebuhr
Thomas C
TC
Pan
Hua
H
Svoboda
Petr
P
Schultz
Richard M
RM
Magnuson
Terry
T
D000107:Acetylation; D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D042002:Chromatin Assembly and Disassembly; D004265:DNA Helicases; D004622:Embryo, Mammalian / Q000502:physiology; D005260:Female; D005298:Fertility; D018507:Gene Expression Regulation, Developmental; D016678:Genome; D006657:Histones / Q000378:metabolism; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D009865:Oocytes / Q000502:physiology; D034622:RNA Interference; D023121:RNA, Messenger, Stored / Q000235:genetics / Q000502:physiology; D011995:Recombination, Genetic; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D015053:Zygote / Q000502:physiology*
D006657:Histones; D009687:Nuclear Proteins; D023121:RNA, Messenger, Stored; D014157:Transcription Factors; C513194:Smarca4 protein, mouse; D004265:DNA Helicases