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PBAF Chromatin-Remodeling Complex Requires a Novel Specificity Subunit, BAF200, to Regulate Expression of Selective Interferon-Responsive Genes

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PBAF Chromatin-Remodeling Complex Requires a Novel Specificity Subunit, BAF200, to Regulate Expression of Selective Interferon-Responsive Genes Downloaded from genesdev.cshlp.org on September 27, 2021 - Published by Cold Spring Harbor Laboratory Press RESEARCH COMMUNICATION tomers to “slide” on DNA (Hamiche et al. 1999; White- PBAF chromatin-remodeling house et al. 1999), or to dissociate from DNA (Lorch et complex requires a novel al. 1999). Because many promoters have defined nucleo- some structures, the repositioning or loss of nucleo- specificity subunit, BAF200, to somes in a regulatory region could lead to either activa- regulate expression of selective tion or repression of transcription. SWI/SNF complexes are evolutionarily conserved interferon-responsive genes from yeast to human, and have been implicated to par- ticipate in many biological processes, such as transcrip- Zhijiang Yan,1 Kairong Cui,2 Darryl M. Murray,1 tional regulation, tumorigenesis, development, and dif- Chen Ling,1 Yutong Xue,1 Amy Gerstein,3 ferentiation (Vignali et al. 2000). They can be grouped Ramon Parsons,3 Keji Zhao,2 and into two major subfamilies: One includes human BAF 1,4 (BRG1 or hbrm-associated factor), Drosophila BAP, and Weidong Wang yeast SWI/SNF; the other comprises human PBAF (Poly- 1Laboratory of Genetics, National Institute on Aging, bromo-associated BAF), Drosophila PBAP, and yeast Baltimore, Maryland 21224, USA; 2Laboratory of Molecular RSC (Cairns et al. 1994, 1996; Cote et al. 1994; Kwon et Immunology, National Heart, Lung, and Blood Institute, al. 1994; Wang et al. 1996; Papoulas et al. 1998; Nie et al. National Institutes of Health, Bethesda, Maryland 20892, 2000; Xue et al. 2000; Mohrmann et al. 2004). These two USA; 3Institute for Cancer Genetics, Columbia University, subfamilies of complexes have similar subunit composi- New York, New York 10032, USA tions, but appear to have different functions (Angus-Hill et al. 2001; Lemon et al. 2001). For example, human BAF PBAF and BAF are two chromatin-remodeling com- and PBAF complexes share eight identical subunits, and plexes of the SWI/SNF family essential for mammalian are distinguished by the presence of only two unique transcription and development. Although these com- subunits: BAF180 (also called Polybromo) for PBAF and BAF250a for BAF (Nie et al. 2000; Xue et al. 2000). De- plexes share eight identical subunits, only PBAF can fa- spite such similarities, only PBAF, but not BAF, is ca- cilitate transcriptional activation by nuclear receptors in pable of facilitating ligand-dependent transcriptional ac- vitro. Here we show that these complexes have selectiv- tivation by nuclear receptors in vitro (Lemon et al. 2001). ity in mediating transcription of different interferon-re- Whether and how these complexes selectively regulate sponsive genes. The selectivity by PBAF requires a novel expression of different genes in vivo remain largely un- subunit, BAF200, but not the previously described clear. Here, we present in vivo evidence that PBAF and PBAF-specificity subunit, BAF180 (Polybromo). Our BAF do have selectivity in regulating interferon-respon- study provides in vivo evidence that PBAF and BAF regu- sive genes. Moreover, we have identified a second speci- late expression of distinct genes, and suggests that ficity subunit for PBAF, termed BAF200, and demon- BAF200 plays a key role in PBAF function. strated that BAF200, but not BAF180, is required for PBAF to mediate expression of an interferon-responsive Supplemental material is available at http://www.genesdev.org. gene, suggesting that BAF200 is an important targeting subunit of PBAF. Received April 15, 2005; revised version accepted May 27, 2005. Results and Discussion The regulation of temporal and spatial gene expression is BAF 200 is a new intrinsic subunit of PBAF complex crucial for normal development and differentiation in We and others have described purification of the two higher eukaryotes. This is ultimately achieved through major human SWI/SNF complexes, BAF (hSWI/SNF-A) delicate cross-talk between the chromatin and the tran- and PBAF (hSWI/SNF-B) (Kwon et al. 1994; Wang et al. scriptional apparatus. Reorganization of chromatin 1996; Nie et al. 2000; Xue et al. 2000; Lemon et al. 2001). structure facilitates or inhibits the access of transcrip- These two complexes share as many as eight common tion factors to their target genes, leading to transcrip- subunits (BRG1, BAF170, BAF155, BAF60a, BAF57, tional activation or repression. Several groups of chro- BAF53, actin, and hSNF5/INI1), but are distinguished by matin-remodeling complexes are responsible for this the presence of two specificity subunits: BAF180 present process (Kornberg and Lorch 1999; Levine and Tjian only in PBAF, and BAF250a exclusively present in BAF 2003). One such group is the SWI/SNF family of remod- (Nie et al. 2000; Xue et al. 2000; Lemon et al. 2001). We eling enzymes, which uses the energy of ATP hydrolysis also noticed the presence of a 200-kDa polypeptide, re- to disrupt the interactions between DNA and histones to ferred to as BAF200, in PBAF complex purified by anti- make the nucleosomal DNA more accessible (Vignali et bodies against BRG1, BAF180, and hSNF5 (Wang et al. al. 2000). The remodeling could also trigger histone oc- 1996; Xue et al. 2000). The fact that this polypeptide is immunopurified by multiple PBAF antibodies strongly suggests that it could be a new component of PBAF. [Keywords: SWI/SNF; BAF; PBAF; RSC; chromatin remodeling; inter- To obtain large amounts of BAF200 for identification, feron] we used an improved immunoprecipitation (IP) protocol 4 Corresponding author. to directly isolate PBAF from HeLa nuclear extract using E-MAIL [email protected]; FAX (410) 558-8331. Article published online ahead of print. Article and publication date are an antibody against BAF180 (the previous purification at http://www.genesdev.org/cgi/doi/10.1101/gad.1323805. used 0.75 M phosphocellulose fraction of HeLa nuclear 1662 GENES & DEVELOPMENT 19:1662–1667 © 2005 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/05; www.genesdev.org Downloaded from genesdev.cshlp.org on September 27, 2021 - Published by Cold Spring Harbor Laboratory Press Chromatin remodeling by PBAF extract). The purity of PBAF complex isolated by the new an integral component of PBAF. A polyclonal anti- protocol is comparable to that obtained by the previous body raised against ARID2 also specifically recognized method (Fig. 1A), and a 200-kDa polypeptide (BAF200) the 200-kDa polypeptide in the PBAF complex iso- was similarly detected. This polypeptide was identi- lated by antibodies to either BAF180 or Flag-hSNF5 (Fig. fied by mass spectrometry as a hypothetical protein of 1B,C), providing further confirmation for ARID2 as 1835 amino acid residues, with the approved gene sym- BAF200. bol of ARID2 (AT-rich interactive domain 2; aliases: To rule out the possibility that BAF200 may indirectly KIAA1557, DKFZp686G052, FLJ30619; gene accession associate with PBAF complex through DNA, IP was ID: NP_689854). carried out in the presence of ethidium bromide (EtBr), We also used mass spectrometry to analyze the 200- a DNA-intercalating drug that dissociates proteins kDa polypeptide in the PBAF complex immunoisolated from DNA. The amount of BAF200 in PBAF was unaf- by the Flag antibody from HeLa cells stably expressing fected by the presence of EtBr (Fig. 1A,B), indicating that Flag-tagged hSNF5/INI1 as described (Xue et al. 2000). BAF200 forms a complex with BAF180 independent of The results confirmed that this polypeptide is ARID2. DNA. The findings that ARID2 is present in PBAF immuno- We also analyzed the Superose 6 gel-filtration profile purified by two independent antibodies indicate that it is of BAF200 in HeLa nuclear extract, and compared it with that of other BAF proteins. The results showed that the profile of BAF200 was identical to that of the PBAF-spe- cific subunit, BAF180, which supports the notion that these two proteins are unique components of the PBAF complex (Fig. 1D). As a comparison, the profiles of BAF200 and BAF180 only partially overlapped with those of BRG1, BAF57, and hSNF5. Because the latter three proteins are shared by many other SWI/SNF com- plexes (including BAF, which is more abundant than PBAF), it is not too surprising that their profiles are dif- ferent from those of BAF200 and BAF180. The expression of BAF200 mRNA was detected by Northern blot analysis in multiple human tissues that have been examined (data not shown). This property re- sembles that of BAF180, as well as some other BAF genes. BAF200 is a new specificity subunit of PBAF and absent in BAF In our previously purified PBAF and BAF complexes from fractionated HeLa nuclear extract, BAF200 was detected only in PBAF, but not BAF, by silver-stained SDS-gel analysis (Nie et al. 2000; Xue et al. 2000). To exclude the possibility that BAF200 may also be a subunit of BAF complex but was dissociated during fractionation of HeLa nuclear extract, we directly immunoisolated PBAF and BAF from unfractionated extract under mild wash- ing conditions (0.3 M salt) using either BAF180 (PBAF) or BAF250a (BAF) antibodies, respectively. Consistent with previous data, BAF200 was detected in only PBAF, but not BAF (Fig. 1E). We also performed reciprocal IP to determine whether Figure 1. BAF200 is a new unique subunit of PBAF. (A) A silver- BAF200-associated polypeptides contain PBAF or BAF stained SDS gel shows the PBAF complex obtained from immuno- components. Because our BAF200 antibody was ineffi- precipitation (IP) by a BAF180 antibody with HeLa nuclear extract in the presence (+) or absence (−) of ethidium bromide (EtBr). Mock IP cient in IP (data not shown), we established a HeLa cell was done by using protein A beads (PnA) alone with the extract. (B) line stably expressing BAF200 tagged with a Flag epitope. Immunoblotting shows the presence of BAF200 in the complex pu- The BAF200-associated polypeptides immunoisolated by rified by BAF180 antibody. The nuclear extract (NE), supernatant the Flag antibody contained the PBAF-specific subunit, (SN), and eluted fraction from IP are indicated.
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