A Brg1 mutation that uncouples ATPase activity from chromatin remodeling reveals an essential role for SWI/SNF-related complexes in beta-globin expression and erythroid development.
The Brg1 catalytic subunit of SWI/SNF-related complexes has been implicated in many developmental and physiological processes, but null homozygotes die as blastocysts prior to implantation. To circumvent this early embryonic lethality, we performed an ENU mutagenesis screen and generated a Brg1 hypomorph mutation in the ATPase domain. The mutant Brg1 protein is stable, assembles into SWI/SNF-related complexes, and exhibits normal ATPase activity but is unable to establish DNase I hypersensitivity sites characteristic of open chromatin. Mutant embryos develop normally until midgestation but then exhibit a distinct block in the development of the erythroid lineage, leading to anemia and death. The mutant Brg1 protein is recruited to the beta-globin locus, but chromatin remodeling and transcription are perturbed. Histone acetylation and DNA methylation are also affected. To our knowledge, Brg1 is the first chromatin-modifying factor shown to be required for beta-globin regulation and erythropoiesis in vivo. Not only does this mutation establish a role for Brg1 during organogenesis, it also demonstrates that ATPase activity can be uncoupled from chromatin remodeling.
Bultman
Scott J
SJ
Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599-7264, USA. scott_bultman@med.unc.edu
Gebuhr
Thomas C
TC
Magnuson
Terry
T
D000107:Acetylation; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D042002:Chromatin Assembly and Disassembly; D004265:DNA Helicases; D019175:DNA Methylation; D004622:Embryo, Mammalian; D004920:Erythropoiesis; D005914:Globins / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D046912:Multiprotein Complexes / Q000502:physiology; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D038081:Organogenesis; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic
D006657:Histones; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D014157:Transcription Factors; D005914:Globins; D000251:Adenosine Triphosphatases; C513194:Smarca4 protein, mouse; D004265:DNA Helicases