Loss of BAF (mSWI/SNF) Complexes Causes Global Transcriptional and Chromatin State Changes in Forebrain Development

• DOI: 10.1016/j.celrep.2015.10.046
• Publication Date: 2015-11-19T13:28:00Z
• Authors: Ramanathan Narayanan; Mehdi Pirouz; Cemil Kerimoglu; Linh Pham; Robin J. Wagener; Kamila A. Kiszka; Joachim Rosenbusch; Rho H. Seong; Michael Kessel; Andre Fischer; Anastassia Stoykova; Jochen F. Staiger; Tran Tuoc
• Keywords: Jumonji Domain-Containing Histone Demethylases; metabolism [Histones]; Chromosomal Proteins, Non-Histone; metabolism [Neural Stem Cells]; Histones; Mice; metabolism [Jumonji Domain-Containing Histone Demethylases]; Neural Stem Cells; deficiency [Chromosomal Proteins, Non-Histone]; metabolism [Histone Demethylases]; metabolism [Transcription Factors]; Utx protein, mouse; cytology [Neural Stem Cells]; Biology (General); Cells, Cultured; Smarcc1 protein, mouse; Histone Demethylases; Mice, Knockout; 0303 health sciences; metabolism [Cerebellar Cortex]; Nuclear Proteins; Cell Differentiation; genetics [Transcription Factors]; genetics [Histones]; Chromatin; DNA-Binding Proteins; Kdm6b protein, mouse; metabolism [Chromosomal Proteins, Non-Histone]; metabolism [DNA Helicases]; metabolism [Nuclear Proteins]; metabolism [Chromatin]; QH301-705.5; Down-Regulation; Mice, Transgenic; genetics [Chromosomal Proteins, Non-Histone]; genetics [Histone Demethylases]; Smarcc2 protein, mouse; Cerebellar Cortex; 03 medical and health sciences; Animals; ddc:610; Smarca4 protein, mouse; metabolism [Embryo, Mammalian]; deficiency [Transcription Factors]; Cell Proliferation; DNA Helicases; Embryo, Mammalian; Mice, Inbred C57BL; Transcription Factors

BAF (Brg/Brm-associated factors) complexes play important roles in development and are linked to chromatin plasticity at selected genomic loci. Nevertheless, a full understanding of their role in development and chromatin remodeling has been hindered by the absence of mutants completely lacking BAF complexes. Here, we report that the loss of BAF155/BAF170 in double-conditional knockout (dcKO) mice eliminates all known BAF subunits, resulting in an overall reduction in active chromatin marks (H3K9Ac), a global increase in repressive marks (H3K27me2/3), and downregulation of gene expression. We demonstrate that BAF complexes interact with H3K27 demethylases (JMJD3 and UTX) and potentiate their activity. Importantly, BAF complexes are indispensable for forebrain development, including proliferation, differentiation, and cell survival of neural progenitor cells. Our findings reveal a molecular mechanism mediated by BAF complexes that controls the global transcriptional program and chromatin state in development.