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SWI/SNF Deficiency Results in Aberrant Chromatin Organization

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SWI/SNF Deficiency Results in Aberrant Chromatin Organization Molecular Biology of the Cell Vol. 20, 3192–3199, July 15, 2009 SWI/SNF Deficiency Results in Aberrant Chromatin Organization, Mitotic Failure, and Diminished Proliferative Capacity Ryan J. Bourgo,* Hasan Siddiqui,† Sejal Fox,‡ David Solomon,§ Courtney G. Sansam,ʈ Moshe Yaniv,¶ Christian Muchardt,¶ Daniel Metzger,# Pierre Chambon,# Charles W.M. Roberts,ʈ and Erik S. Knudsen* *Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107; †Human Cancer Genetics Program, Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, College of Medicine and Public Health, The Ohio State University, Columbus, OH 43210; ‡Department of Cell and Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267; §Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, DC, 20057; ¶Expression Ge´ne´tique et Maladies, Formation de Recherche en Evolution 2850 du Centre National de la Recherche Scientifique, De´partement de Biologie du De´veloppement, Institut Pasteur, 75724 Paris, France; #Institut de Ge´ne´tique et Biologie Mole´culaire et Cellulaire, Department of Functional Genomics, F-67400 Illkirch, France; Institut National de la Sante´ et de la Recherche Me´dicale, U596, F-67400 Illkirch, France; Centre National de la Recherche Scientifique, Unite´ Mixte de Recherche 7104, F-67400 Illkirch, France; Universite´ Louis Pasteur, F-67000 Strasbourg, France; Colle´ge de France, F-67400 Illkirch, France; and ʈDepartment of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115 Submitted December 19, 2008; Revised April 13, 2009; Accepted May 11, 2009 Monitoring Editor: J. Silvio Gutkind Switch (SWI)/sucrose nonfermentable (SNF) is an evolutionarily conserved complex with ATPase function, capable of regulating nucleosome position to alter transcriptional programs within the cell. It is known that the SWI/SNF complex is responsible for regulation of many genes involved in cell cycle control and proliferation, and it has recently been implicated in cancer development. The ATPase action of SWI/SNF is conferred through either the brahma-related gene 1 (Brg1) or brahma (Brm) subunit of the complex, and it is of central importance to the modification of nucleosome position. In this study, the role of the Brg1 and Brm subunits were examined as they relate to chromatin structure and organization. Deletion of the Brg1 ATPase results in dissolution of pericentromeric heterochromatin domains and a redistribution of histone modifications associated with these structures. This effect was highly specific to Brg1 and is not reproduced by the loss of Brm or SNF5/BAF47/INI1. Brg1 deficiency is associated with the appearance of micronuclei and aberrant mitoses that are a by-product of dissociated chromatin structure. Thus, Brg1 plays a critical role in maintaining chromatin structural integrity. INTRODUCTION both Brg1 and Brm can function as the central ATPase in the SWI/SNF complex, each defines a discrete complex with The switch/sucrose nonfermentable (SWI/SNF) complex unique biochemical activity. In addition, specific accessory uses the energy of ATP hydrolysis to modulate nucleosome factors interact with the ATPase subunits and play critical position and density across promoters and thus plays an roles in chromatin remodeling activity. For example, SNF5/ important role in regulating gene expression. The SWI/SNF BAF47/INI1 is present in both Brg1- and Brm-associated ATPase function is necessary for its chromatin remodeling complexes and is required for maximal chromatin remodel- activities (Laurent et al., 1993), and this function is mani- ing activity, both in vitro and in yeast. Surprisingly, al- fested through one of two mutually exclusive subunits, though Brg1 and Brm have Ͼ75% sequence homology, the brahma-related gene 1 (Brg1) or brahma (Brm). Although impact of each individual subunit on chromatin biology and underlying cell biology is poorly understood (Phelan et al., 1999). This article was published online ahead of print in MBC in Press Due to its central function in chromatin remodeling, SWI/ (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E08–12–1224) SNF function is required in many facets of gene regulation. on May 20, 2009. Correspondingly, it is estimated that approximately 5% of Address correspondence to: Ryan J. Bourgo (ryan.bourgo@jefferson. the yeast genome is transcriptionally regulated by the SWI/ edu). SNF complex (Holstege et al., 1998; Sudarsanam et al., 2000). Abbreviations used: Brg1, brahma-related gene 1; Brm, brahma; RB, In mammalian cells, SWI/SNF plays a critical role in the retinoblastoma; SNF, sucrose nonfermentable; SNF5, SNF5/BAF47/ activation of a diverse set of genes and has been shown to be INI1; SWI, switch. recruited directly to transcriptional activation domains (De- 3192 © 2009 by The American Society for Cell Biology SWI/SNF Deficiency Causes Failed Mitosis roo and Archer, 2001; Hassan et al., 2001). In contrast, SWI/ analyzed by PCR using a combination of three different primers: sense 5Ј- Ј Ј SNF is also required for transcriptional repression. For ex- CCTGAGTCATTTGCTATAGCCTGTG-3 , antisense 5 -GGACTGCCAGCT- GCA-GAG-3Ј, and 5Ј-CATCGCCTTCTAT-CGCCTTC-3Ј. For mouse genotyp- ample, transcriptional repression of cell cycle genes ing (Brg1), mouse tail DNA was extracted and analyzed by using the mediated by the retinoblastoma tumor suppressor is depen- following primers: sense 5Ј-GATCAGCTCATGCCCTAAGG-3Ј and antisense dent on SWI/SNF, implicating the involvement of SWI/SNF 5Ј-CCTACAGTTCCATG-CAGCTGG-3Ј. in cellular proliferation (Gunawardena et al., 2004, 2007). Paradoxically, disruption of SWI/SNF function has alter- Retroviral Transduction, Plasmid Transfection, and natively been associated with tumorigenesis and lack of Selection cellular/organismal viability. Specifically, loss or mutation of the SNF5/INI1 subunit is associated with rhabdoid tu- Retroviral Transduction. Cells were transduced for 7 h with a retrovirus morigenesis, and it has been convincingly demonstrated that containing a p53 dominant-negative allele (p53DD). The transduced cells were selected for 14 d in 0.2 mg/ml G418 sulfate (Calbiochem, San Diego, CA). the SNF5/INI1 gene acts as a tumor suppressor (Biegel et al., 1999; Sevenet et al., 1999; Roberts et al., 2002). Correspond- Plasmid Transfection. Cells were transfected for 18 h using Lipofectin trans- ingly, diminished expression or loss of Brg1, Brm, Baf57, fection reagent (Invitrogen, Carlsbad, CA) following manufacturer-provided Baf180, and several other chromatin-modifying genes has protocol. After 48 h, cells were passaged into 2 ␮g/ml puromycin for 7 d. been observed in cancer cell lines and tumor specimens These cells were passaged again into 2 ␮g/ml puromycin for another 7 d (Gregory and Shiekhattar, 2004). However, these implica- before beginning experimental procedures. tions in tumor development are seemingly at odds with important roles for SWI/SNF subunits in maintaining cellu- RESULTS lar viability and proliferative capacity (Bultman et al., 2000). It is well known that chromosomal instability is a hall- Targeted Deletion of SWI/SNF ATPases in Cell Culture mark of cancer. Interestingly, loss of chromatin regulatory The SWI/SNF complex is implicated in a wide range of proteins can have deleterious effects on chromatin structure highly cancer-relevant processes, such as transcriptional reg- that can compromise genome stability and fuel tumorigen- ulation, cell cycle control, and DNA repair. Here, models of esis (David et al., 2003, 2006). Here, we used somatic cell Brg1 and Brm knockout were used to directly define the culture models to define the impact of the SWI/SNF chro- impact of deficiency of these subunits on cellular function. matin-modifying complex on chromatin biology and cell To perform these studies, we utilized mouse adult fibro- Ϫ Ϫ cycle progression. blasts that were derived from Brg1f/f, Brm / , and com- pound BrmϪ/ϪBrg1f/f mice. By employing Cre-recombinase in vitro, any combination of core ATPase deficiency could be MATERIALS AND METHODS created (Supplemental Figure S1A). Cell cultures were trans- Cell Culture and Adenoviral Transduction duced with adenoviruses encoding either GFP or GFP-Cre, Ͼ Primary and 3T3 cell lines were cultured in DMEM supplemented with 10% and analyses of GFP-fluorescence revealed 95% of cells heat-inactivated fetal bovine serum, 100 U/ml penicillin-streptomycin, and 2 were infected. Correspondingly, the Brg1lox allele was effi- mM l-glutamine at 37°C in 5% CO2. All cell lines were transduced with ciently recombined in those cultures subjected to infection adenoviruses encoding green fluorescent protein (GFP), GFP-Cre recombi- with GFP-Cre encoding adenoviruses (Supplemental Figure nase (Cre), or Cre for 120 h. S1B). Consistent with the genetic recombination, the expres- Immunoblotting sion of Brg1 protein was significantly reduced at 120 h after Cell lysates were resolved by SDS-polyacrylamide gel electrophoresis (PAGE) infection (Figure 1A). As expected, the Brm knockout cell and transferred to Immobilon-P membrane (Millipore, Billerica, MA). Mem- cultures exhibited the appropriate genomic organization of branes were incubated with the following primary antibodies: Brg1 (sc-17796; the targeted allele and failed to express Brm protein (Figure Santa Cruz Biotechnology, Santa Cruz, CA), Brm (sc-17828; Santa Cruz Biotech- 1A). Thus, each combination of ATPase deficiency could be nology), vimentin (gift from Dr. Wallace
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