title: Dual role of Brg chromatin remodeling factor in Sonic hedgehog signaling during neural development.
abstract: Sonic hedgehog (Shh) signaling plays diverse roles during animal development and adult tissue homeostasis through differential regulation of Gli family transcription factors. Dysregulated Shh signaling activities have been linked to birth defects and tumorigenesis. Here we report that Brg, an ATP-dependent chromatin remodeling factor, has dual functions in regulating Shh target gene expression. Using a Brg conditional deletion in Shh-responding neural progenitors and fibroblasts, we demonstrate that Brg is required both for repression of the basal expression and for the activation of signal-induced transcription of Shh target genes. In developing telencephalons deficient for Brg, Shh target genes were derepressed, whereas Brg-deleted cerebellar granule neuron precursors failed to respond to Shh to increase their proliferation. The repressor function of Brg was mediated through Gli3 and both the repressor and activator functions of Brg appeared to be independent of its ATPase activity. Furthermore, Brg facilitates Gli coactivator histone deacetylase (HDAC) binding to the regulatory regions of Shh target genes, providing a possible mechanism for its positive role in Shh signaling. Our results thus reveal that a complex chromatin regulation mechanism underlies the precise transcription outcomes of Shh signaling and its diverse roles during development.
authors.affiliation: Department of Physiology and Developmental Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9133, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zhan
authors.forename: Xuanming
authors.initials: X
authors.lastname: Shi
authors.forename: Zilai
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.forename: Jiang I
authors.initials: JI
authors.lastname: Wu
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly / Q000235:genetics / Q000502:physiology; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D017403:In Situ Hybridization; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013687:Telencephalon / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D046509:Tissue Culture Techniques; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000074290:Zinc Finger Protein Gli3
chemical_list: C465571:Gli3 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D000074290:Zinc Finger Protein Gli3; D006655:Histone Deacetylases; C513194:Smarca4 protein, mouse; D004265:DNA Helicases