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Dual Role of Brg Chromatin Remodeling Factor in Sonic Hedgehog Signaling During Neural Development

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Dual Role of Brg Chromatin Remodeling Factor in Sonic Hedgehog Signaling During Neural Development Dual role of Brg chromatin remodeling factor in Sonic hedgehog signaling during neural development Xiaoming Zhan1, Xuanming Shi1, Zilai Zhang, Yu Chen, and Jiang I. Wu2 Department of Physiology and Developmental Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9133 Edited* by Matthew P. Scott, Stanford University/Howard Hughes Medical Institute, Stanford, CA, and approved June 20, 2011 (received for review December 13, 2010) Sonic hedgehog (Shh) signaling plays diverse roles during animal bility (19, 20). In addition, their 10–12 subunits provide surfaces to development and adult tissue homeostasis through differential interact with various transcription factors and cofactors (21, 22), regulation of Gli family transcription factors. Dysregulated Shh which may introduce additional ATPase-independent functions signaling activities have been linked to birth defects and tumor- to BAF complexes as activators or repressors. igenesis. Here we report that Brg, an ATP-dependent chromatin In this study, we found that during neural development, Brg, remodeling factor, has dual functions in regulating Shh target the ATPase subunit of BAF complexes, plays a dual role in gene expression. Using a Brg conditional deletion in Shh-responding regulating Shh signaling. It is required for both repression of the neural progenitors and fibroblasts, we demonstrate that Brg is basal expression and for the activation of signal-induced Shh target gene transcription. In neural progenitors and fibroblasts, required both for repression of the basal expression and for the conditional deletion of Brg resulted in altered Shh target gene activation of signal-induced transcription of Shh target genes. In fi expression and defective response to Shh signal. Brg interacted developing telencephalons de cient for Brg, Shh target genes with Gli transcription factors and was likely recruited to Gli were derepressed, whereas Brg-deleted cerebellar granule neuron regulatory regions. Both Brg repressor and activator functions precursors failed to respond to Shh to increase their proliferation. appear to be independent of its ATPase activity and its coac- The repressor function of Brg was mediated through Gli3 and both tivator function was at least partially mediated through facili- the repressor and activator functions of Brg appeared to be tating HDAC coactivator binding to the Gli regulatory regions. independent of its ATPase activity. Furthermore, Brg facilitates Thus, our results uncovered an essential epigenetic program Gli coactivator histone deacetylase (HDAC) binding to the regula- regulating Shh target gene expression. tory regions of Shh target genes, providing a possible mechanism for its positive role in Shh signaling. Our results thus reveal that Results a complex chromatin regulation mechanism underlies the precise Brg Represses the Basal Expression of Shh Target Genes in Developing transcription outcomes of Shh signaling and its diverse roles Telencephalons. Our previous analysis of a neural-specific Brg during development. conditional knockout (BrgF/F; Nestin-Cre) indicated that the Brg/ BAF complex is essential for cortical neural progenitor self- Gli proteins | neural development | SWI/SNF complexes | renewal, maintenance, and proper differentiation (23). Microarray transcription regulation | signal transduction analysis revealed that levels of a group of Shh target genes, in- cluding Ptch1, Hhip, olig2, and pdgfra, were significantly increased he Sonic hedgehog (Shh) signaling pathway regulates many in embryo day 12.5 (E12.5) Brg-mutant telencephalon compared Timportant mammalian development processes (1–4). During with levels in wild-type tissue (23). The Ptch1 gene encodes a Shh neural development, Shh exerts different functions as a mor- receptor and is also a direct Shh target gene. Using a Ptch1-lacZ indicator mouse with a lacZ gene knocked in at the Ptch1 locus phogen or a mitogen. For example, in telencephalons, Shh fi mainly antagonizes Gli3 repressor function to regulate the dor- (24), we con rmed that Ptch1 gene expression was increased in sal–ventral neural patterning (2, 3, 5, 6). In contrast, during Brg-deleted neural tissues such as telencephalons and neural cerebellum development, Shh produced from Purkinje neurons tubes (Fig. 1A). activates mitogenic target genes in cerebellar granule neuron Expression of other Shh target genes in Brg-mutant tele- – ncephalons was examined (Fig. 1 B and C). Olig2 expression was precursors (CGNP) that result in CGNP proliferation (7 9). fi Shh signaling controls target gene expression by regulating signi cantly derepressed in the cortex and dorsal diencephalon activities of Gli family transcription factors (1, 2, 10). Three Gli regions as shown by antibody staining (Fig. 1B, arrows). In proteins (Gli1, -2, and -3) perform distinct and partially over- contrast, Olig2 expression in the basal ganglia eminence and lapping functions (2, 11). Gli1 and Gli2 are the main transcrip- ventral diencephalon was reduced (Fig. 1B, arrowheads), sug- tion activators mediating Shh-induced transcription. Gli3 can be gesting additional function of Brg in Shh-induced gene activation (see below). We confirmed by RT-PCR that expression of other proteolysed in the absence of Shh signals and the C-terminal fi truncated proteins function as the main repressor for Shh target universal and neural-speci c Shh target genes such as Gli1, Hhip, genes (12). Shh signaling inhibits Gli3 proteolysis and activates and Nkx6.2 was increased in the mutants, especially in the dorsal Gli1/2 proteins. In general, Gli proteins share the same set of cortex region (Fig. 1D, Upper). Expression of general ventral telencephalon markers such as Mash1 and Gsh2 were not sig- target genes (13). However, the chromatin cofactors essential for fi fi distinct Gli transcription activities during development are ni cantly changed (Fig. 1D), suggesting a speci c requirement of largely unknown. One epigenetic mechanism of Gli3 repressing Brg for regulating Shh target genes. Importantly, Shh, Gli3, and Shh target genes is by recruiting histone deacetylase (HDAC) corepressors, which likely repress transcription by deacetylating histones (14, 15). Interestingly, it has been recently reported that Author contributions: X.Z. and J.I.W. designed research; X.Z., X.S., Z.Z., Y.C., and J.I.W. HDAC1/2 positively regulate transcription activator activity of performed research; X.Z., X.S., Z.Z., and J.I.W. analyzed data; and X.Z. and J.I.W. wrote the paper. Gli1 by directly controlling Gli1 protein deacetylation (16). Thus, fl Gli transcription activities and Shh signaling outcomes are under The authors declare no con ict of interest. complex regulations by chromatin regulators. *This Direct Submission article had a prearranged editor. The mammalian SWI/SNF-like Brg/Brm associated factor 1X.Z. and X.S. contributed equally to this work. (BAF) complexes are ATP-dependent chromatin remodeling 2To whom correspondence should be addressed. E-mail: [email protected]. complexes (17, 18), which can use energy derived from ATP hy- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. drolysis to regulate nucleosome mobility and chromatin accessi- 1073/pnas.1018510108/-/DCSupplemental. 12758–12763 | PNAS | August 2, 2011 | vol. 108 | no. 31 www.pnas.org/cgi/doi/10.1073/pnas.1018510108 Downloaded by guest on October 2, 2021 A D CreER) (27), addition of 4-hydroxytamoxifen (4-OHT) induces BrgF/F BrgF/F, Nestin-Cre Dorsal Ventral Brg deletion and reduced Brg protein to undetectable levels wt mut2 mut1 mut2 mut1 wt within 48 h. In Brg-mutant MEF cells, we also observed increased Ptch1 expression of Shh target genes such as Gli1 and Ptch1 (Fig. 2A). Olig2 Treatment with cyclopamine decreased the expression of Shh Ptch1-LacZ target genes in both wild-type and Brg-mutant MEF cells (Fig. Hhip 2A). However, their basal expression levels in Brg-mutant cells B Nkx6.2 ctx ctx were significantly higher (Fig. 2A), supporting the notion that Brg Di Di Gli1 is required to repress the basal expression of Shh target genes. In control experiments, addition of 4-OHT to wild-type MEF cells Olig2 BGE BGE Gsh2 did not affect Shh target gene expression (Fig. S1). Thus, as are Mash1 telencephalons, cultured MEF cells are suitable for studying BAF C Gli3 regulation of Shh signaling pathway. Gli2 Because Gli1 level is most sensitive to Brg deletion, we next Shh focused our studies using Gli1 to represent Shh target genes. Nkx6.2 GAPDH Reintroducing exogenous Brg into Brg-mutant MEF cells did re- store the repression of Gli1 basal expression (Fig. 2B), suggesting a direct role of Brg in repressing Shh target genes. Interestingly an * ATPase inactive form of Brg protein, BrgK785R (17), efficiently E WT Brg-mut F wt * p<0.01 mut repressed Gli1 expression (Fig. 2B), suggesting that the repression DDVV wt/cyA * mut/cyA function of Brg is independent of its ATPase activity. Gli3-FL * * * Because Gli3 is the main transcription factor that represses Shh Gli3-R * target genes, we examined the functional relationship between Brg and Gli3. Deletion of Brg or Gli3 individually by either RNAi Brg * * Relative mRNA level Relative knockdown or knockout in MEF cells derepressed Gli1 mRNA −/− Hsp90 expression (Fig. 2C). Notably, deletion of Brg from Gli3 MEF cells resulted in a decrease of Gli1 expression relative to levels in Gli1 Hhip Nkx6.2 Olig2 − − Gli3 / MEF cells (Fig. 2C). The lack of additive effects between Fig. 1. Shh target genes are derepressed in Brg-mutant telencephalon Gli3 and Brg deletion indicates that Brg repressor function neural progenitors. (A) Whole mount β-galactosidase staining of E13.5 wild- requires the presence of Gli3. The decreased Gli1 level resulted − − type and Brg neural specific conditional knockout embryos containing from Brg knockdown in Gli3 / MEFs suggests that Brg is re- a ptch1-LacZ knockin allele. (B) Immunostaining of Olig2 on coronal sections quired for the full expression of Gli1 in the absence of Gli3 (Fig. of E13 wild-type and Brg-mutant brain. ctx, cortex; BGE, basal ganglia em- 2C). Furthermore, exogenous wild-type Brg and BrgK785R mu- inence; Di, diencephalon.
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