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Supplemental InformationLibrary preparation for ChIP-Seq and ChIP-RX. For ChIP-seq, samples were incubated 10 minutes at 4? C in Lysis Buffer 1 (50 mM HEPES , pH 7.5, 140 mM NaCl, 1 mM EDTA, 10% glycerol, 0.5% IGEPAL, 0.25% Triton X-100, 1X HALT protease inhibitor) and then collected by spinning at 1350 G for 5 minutes. Samples were resuspended in Lysis Buffer 2 (10 mM Tris pH 8, 200 mM NaCl, 1 mM EDTA, 0.5mM EGTA, 1X HALT protease inhibitor), again incubated 10 minutes at 4? C and spun at 1350 G for 5 minutes. Samples were resuspended in sonication buffer ( 0.1% Na-Deoxycholate, 50 mM HEPES pH 7.5, 140 mM NaCl, 1 mM EDTA, 1mM EGTA, 1% Triton X-100, 1X HALT protease inhibitor) with SDS added to a final concentration of 0.5%. Then, samples were sonicated in 15 mL conical TPX tubes with a Bioruptor (Diagenode) for 25 cycles (30 seconds on and 30 seconds off on a high power setting. Sonicated samples were clarified by spinning 10 minutes at 20,000 G. 50 uL of supernatant was set aside as non-IP input control. Remaining supernatant was diluted 1:5 in sonication buffer and each sample incubated overnight at 4? C with 100 uL of Protein G Dynabeads (Life Technologies) bound with 10 micrograms of anti-H3K27Ac antibody (ab4729, Abcam). Beads were collected via magnet and washed while rotating end-over-end at 4? C in the following buffers: twice in sonication buffer, once in modified sonication buffer with NaCl added to a final concentration of 500 mM, once in LiCl wash buffer (20 mM Tris pH 8, 1 mM EDTA, 25 mM LiCl, 0.5% IGEPAL, 0.5% Na-Deoxycholate), and once in TE-NaCl buffer (50 mM Tris pH 8, 50 mM NaCl). Dynabeads were finally resuspended in 200 uL elution buffer (50 mM Tris pH 8, 1 mM EDTA, 1% SDS) and heated for 15 minutes at 65? C. Samples were spun at 20,000 G for 30 seconds to collect beads and supernatant was collected. 150 uL of elution buffer was added to input chromatin samples. Eluted samples and corresponding input chromatin samples were incubated at 65? C 16 hours to reverse crosslinks. All samples were then incubated with RNAse A (Thermo Scientific) for 2 hours at 37? C and then 30 minutes at 55? C with Proteinase K (Ambion). DNA was isolated via phenol-chloroform extraction followed by ethanol precipitation. NGS libraries were generated with Thruplex DNAseq Single Index Kit (Rubicon) and sequenced (single end, 75 bp reads) via NextSeq 500.ChIP-seq data processing.Sequence alignment. All datasets were aligned using Bowtie2 (version 2.2.1) to build version NCBI37/HG19. ADDIN EN.CITE <EndNote><Cite><Author>Langmead</Author><Year>2009</Year><RecNum>1</RecNum><DisplayText><style face="superscript">1</style></DisplayText><record><rec-number>1</rec-number><foreign-keys><key app="EN" db-id="ewttf2szlfsrrmeewx8xfxplf0est0vsae00" timestamp="1489158706">1</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Langmead, Ben</author><author>Trapnell, Cole</author><author>Pop, Mihai</author><author>Salzberg, Steven L.</author></authors></contributors><titles><title>Ultrafast and memory-efficient alignment of short DNA sequences to the human genome</title><secondary-title>Genome biology</secondary-title></titles><periodical><full-title>Genome biology</full-title></periodical><volume>10</volume><number>3</number><dates><year>2009</year></dates><isbn>1474-7596</isbn><urls><related-urls><url> Alignments were performed using all default parameters except for –k 1. Calculating read density. We calculated the normalized read density of a ChIP-Seq dataset in any genomic region using the Bamliquidator (version 1.0) read density calculator (). Briefly, ChIP-Seq reads aligning to the region were extended by 200bp and the density of reads per base pair (bp) was calculated. For ChIP-seq, the density of reads in each region was normalized to the total number of million mapped reads producing read density in units of reads per million mapped reads per bp (rpm/bp). For ChIP-Rx (as described below), the density of reads in each region was normalized to the total number of reads originating from the reference exogenous genome (reference adjusted reads per million, rrpm) producing units of rrpm per base pair (rrpm/bp).Identifying enriched regions. We used the MACS version 1.4.1 (Model based analysis of ChIP-Seq) 67 peak finding algorithm to identify regions of ChIP-Seq enrichment over background. ADDIN EN.CITE <EndNote><Cite><Author>Zhang</Author><Year>2008</Year><RecNum>2</RecNum><DisplayText><style face="superscript">2</style></DisplayText><record><rec-number>2</rec-number><foreign-keys><key app="EN" db-id="ewttf2szlfsrrmeewx8xfxplf0est0vsae00" timestamp="1489158706">2</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Zhang, Yong</author><author>Liu, Tao</author><author>Meyer, Clifford A.</author><author>Eeckhoute, Jér?me</author><author>Johnson, David S.</author><author>Bernstein, Bradley E.</author><author>Nusbaum, Chad</author><author>Myers, Richard M.</author><author>Brown, Myles</author><author>Li, Wei</author><author>Liu, X. S.</author></authors></contributors><titles><title>Model-based analysis of ChIP-Seq (MACS)</title><secondary-title>Genome biology</secondary-title></titles><periodical><full-title>Genome biology</full-title></periodical><volume>9</volume><number>9</number><dates><year>2008</year></dates><isbn>1474-7596</isbn><urls><related-urls><url> A p value threshold of enrichment of 1e-9 was used for all datasets. Defining active genes. Across samples active genes were defined as those with an enriched region in at least one cell line in the +/- 1kb region flanking the transcription start site (TSS). This resulted in 16,410 active genes defined in UPS.Mapping typical enhancers and super-enhancers using H3K27ac enhancer definitions. H3K27ac super-enhancers (SEs) and typical enhancers (TEs) were mapped using the ROSE2 software package described in Brown, et al. (2014) and available at (ROSE2_main.py). ADDIN EN.CITE <EndNote><Cite><Author>Brown</Author><Year>2014</Year><RecNum>3</RecNum><DisplayText><style face="superscript">3</style></DisplayText><record><rec-number>3</rec-number><foreign-keys><key app="EN" db-id="ewttf2szlfsrrmeewx8xfxplf0est0vsae00" timestamp="1489158706">3</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Brown, Jonathan D.</author><author>Lin, Charles Y.</author><author>Duan, Qiong</author><author>Griffin, Gabriel</author><author>Federation, Alexander J.</author><author>Paranal, Ronald M.</author><author>Bair, Steven</author><author>Newton, Gail</author><author>Lichtman, Andrew H.</author><author>Kung, Andrew L.</author><author>Yang, Tianlun</author><author>Wang, Hong</author><author>Luscinskas, Francis W.</author><author>Croce, Kevin J.</author><author>Bradner, James E.</author><author>Plutzky, Jorge</author></authors></contributors><titles><title>NF-κB Directs Dynamic Super Enhancer Formation in Inflammation and Atherogenesis</title><secondary-title>Molecular Cell</secondary-title></titles><periodical><full-title>Molecular Cell</full-title></periodical><pages>219-231</pages><volume>56</volume><number>2</number><dates><year>2014</year></dates><publisher>sciencedirect</publisher><isbn>1097-2765</isbn><urls><related-urls><url> Drive/Publications/Brown et al-2014-Mol Cell.pdf</url></pdf-urls></urls><electronic-resource-num>10.1016/j.molcel.2014.08.024</electronic-resource-num><remote-database-name>READCUBE</remote-database-name></record></Cite></EndNote>3 Default parameters, including exclusion of TSS-proximal signal (within 2.5 kb), were used and a stitching parameter was determined that consolidated proximal peaks while optimizing the enriched fraction of stitched peaks (as per default settings of ROSE2 software package). Creating meta representations of ChIP-Seq occupancy. Meta plots of ChIP-Seq occupancy for H3K27ac were created as in Lin, et al. (2012) for enhancers as defined above. ADDIN EN.CITE <EndNote><Cite><Author>Lin</Author><Year>2012</Year><RecNum>4</RecNum><DisplayText><style face="superscript">4</style></DisplayText><record><rec-number>4</rec-number><foreign-keys><key app="EN" db-id="ewttf2szlfsrrmeewx8xfxplf0est0vsae00" timestamp="1489158706">4</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lin, C. Y.</author><author>Loven, J.</author><author>Rahl, P. B.</author><author>Paranal, R. M.</author><author>Burge, C. B.</author><author>Bradner, J. E.</author><author>Lee, T. I.</author><author>Young, R. A.</author></authors></contributors><auth-address>Whitehead Institute for Biomedical Research, Cambridge Center, MA 02142, USA.</auth-address><titles><title>Transcriptional amplification in tumor cells with elevated c-Myc</title><secondary-title>Cell</secondary-title><alt-title>Cell</alt-title></titles><periodical><full-title>Cell</full-title><abbr-1>Cell</abbr-1></periodical><alt-periodical><full-title>Cell</full-title><abbr-1>Cell</abbr-1></alt-periodical><pages>56-67</pages><volume>151</volume><number>1</number><keywords><keyword>Cell Line, Tumor</keyword><keyword>Cell Proliferation</keyword><keyword>Enhancer Elements, Genetic</keyword><keyword>*Gene Expression Regulation, Neoplastic</keyword><keyword>Humans</keyword><keyword>Neoplasms/*genetics/pathology</keyword><keyword>Promoter Regions, Genetic</keyword><keyword>Proto-Oncogene Proteins c-myc/*metabolism</keyword><keyword>Transcription, Genetic</keyword></keywords><dates><year>2012</year><pub-dates><date>Sep 28</date></pub-dates></dates><isbn>1097-4172 (Electronic)
0092-8674 (Linking)</isbn><accession-num>23021215</accession-num><urls><related-urls><url> Each row plots the +/-10 kb region flanking the enhancer center and is divided into 200 bins of 100 bp each. Underlying metas represent the average signal for all each bin in each flanking region. Scaling cell count normalized ChIP-Rx datasets. Scale factors (million mapped reads of reference exogenous genome) for each ChIP-Rx dataset were calculated as in Orlando, et al. (2014) with the exception that mouse genomic reads were calculated instead of drosophila genomic reads. ADDIN EN.CITE <EndNote><Cite><Author>Orlando</Author><Year>2014</Year><RecNum>5</RecNum><DisplayText><style face="superscript">5</style></DisplayText><record><rec-number>5</rec-number><foreign-keys><key app="EN" db-id="ewttf2szlfsrrmeewx8xfxplf0est0vsae00" timestamp="1489158706">5</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Orlando, David A.</author><author>Chen, Mei</author><author>Brown, Victoria E.</author><author>Solanki, Snehakumari</author><author>Choi, Yoon J.</author><author>Olson, Eric R.</author><author>Fritz, Christian C.</author><author>Bradner, James E.</author><author>Guenther, Matthew G.</author></authors></contributors><titles><title>Quantitative ChIP-Seq Normalization Reveals Global Modulation of the Epigenome</title><secondary-title>Cell Reports</secondary-title></titles><periodical><full-title>Cell Reports</full-title></periodical><volume>9</volume><number>3</number><dates><year>2014</year></dates><isbn>2211-1247</isbn><urls><related-urls><url> Drive/Publications/Techniques/Orlando_CellReports_2014.pdf</url></pdf-urls></urls><electronic-resource-num>10.1016/j.celrep.2014.10.018</electronic-resource-num><remote-database-name>READCUBE</remote-database-name></record></Cite></EndNote>5 Briefly, ChIP-Rx datasets, which were produced from equal cell number inputs, were scaled by scale factors to create Y-axis arbitrary units (reference-adjusted reads per million, rrpm) to normalize difference in occupancy per cell.Creating boxplot representations of ChIP-Seq signal load. Total read counts in each super enhancer as reported by Bamliquidator via the ROSE2 package were tallied for all super-enhancers and those super-enhancers assigned by the ROSE2 package to NFKB associated genes as defined by the Hallmark M5890 gene set referred to as “TNFA signaling via NF-B.”Construction of core regulatory circuitry. Core regulatory circuitry (CRC) was constructed as in Saint-Andre, et al. (2016) using the freely available CRC Mapper package ().PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYWludC1BbmRyZTwvQXV0aG9yPjxZZWFyPjIwMTY8L1ll
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ADDIN EN.CITE.DATA 6 Briefly, the set of actively expressed transcription factors (TFs) was defined as those ranking in the top 66% percent of TFs by H3K27ac ChIP-seq signal at the promoter, as well as NF-?B subunits. Transcription factor position weight matrices (PWMs) were obtained from TRANSFAC,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXR5czwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 10 mouse UniPROBE, ADDIN EN.CITE <EndNote><Cite><Author>Robasky</Author><Year>2011</Year><RecNum>29</RecNum><DisplayText><style face="superscript">11</style></DisplayText><record><rec-number>29</rec-number><foreign-keys><key app="EN" db-id="ewttf2szlfsrrmeewx8xfxplf0est0vsae00" timestamp="1489327761">29</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Robasky, K.</author><author>Bulyk, M. L.</author></authors></contributors><auth-address>Department of Medicine, Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.</auth-address><titles><title>UniPROBE, update 2011: expanded content and search tools in the online database of protein-binding microarray data on protein-DNA interactions</title><secondary-title>Nucleic Acids Res</secondary-title></titles><periodical><full-title>Nucleic Acids Res</full-title></periodical><pages>D124-8</pages><volume>39</volume><number>Database issue</number><keywords><keyword>Animals</keyword><keyword>Binding Sites</keyword><keyword>DNA/chemistry/metabolism</keyword><keyword>DNA-Binding Proteins/chemistry/*metabolism</keyword><keyword>*Databases, Protein</keyword><keyword>Humans</keyword><keyword>Internet</keyword><keyword>Protein Array Analysis</keyword><keyword>Sequence Analysis, Protein</keyword><keyword>Software</keyword></keywords><dates><year>2011</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1362-4962 (Electronic)
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ADDIN EN.CITE.DATA 12 FIMO was used to find motifs in predicted nucleosome free regions of TF associated enhancers and promoters. ADDIN EN.CITE <EndNote><Cite><Author>Grant</Author><Year>2011</Year><RecNum>33</RecNum><DisplayText><style face="superscript">13</style></DisplayText><record><rec-number>33</rec-number><foreign-keys><key app="EN" db-id="ewttf2szlfsrrmeewx8xfxplf0est0vsae00" timestamp="1489328259">33</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Grant, C. E.</author><author>Bailey, T. L.</author><author>Noble, W. S.</author></authors></contributors><auth-address>Department of Genome Sciences, University of Washington, Seattle, WA, USA.</auth-address><titles><title>FIMO: scanning for occurrences of a given motif</title><secondary-title>Bioinformatics</secondary-title></titles><periodical><full-title>Bioinformatics</full-title></periodical><pages>1017-8</pages><volume>27</volume><number>7</number><keywords><keyword>*Amino Acid Motifs</keyword><keyword>Base Sequence</keyword><keyword>Binding Sites</keyword><keyword>Conserved Sequence</keyword><keyword>DNA/*chemistry</keyword><keyword>Databases, Genetic</keyword><keyword>Genome, Human</keyword><keyword>Humans</keyword><keyword>Position-Specific Scoring Matrices</keyword><keyword>Repressor Proteins/metabolism</keyword><keyword>Sequence Analysis, DNA/*methods</keyword><keyword>Sequence Analysis, Protein/*methods</keyword><keyword>*Software</keyword></keywords><dates><year>2011</year><pub-dates><date>Apr 01</date></pub-dates></dates><isbn>1367-4811 (Electronic)
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ADDIN EN.CITE.DATA 14 RNA-seq reads were aligned to the transcriptome using Tophat2 with 35 bp chunk size. Transcripts were quantified using cuffquant and cuffnorm was used to obtain transcript counts. The raw gene counts were entered into edgeR for differential gene expression analysis to calculate fold change in transcript counts and p-values. ADDIN EN.CITE <EndNote><Cite><Author>Robinson</Author><Year>2010</Year><RecNum>35</RecNum><DisplayText><style face="superscript">15</style></DisplayText><record><rec-number>35</rec-number><foreign-keys><key app="EN" db-id="ewttf2szlfsrrmeewx8xfxplf0est0vsae00" timestamp="1489424469">35</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Robinson, M. D.</author><author>McCarthy, D. J.</author><author>Smyth, G. K.</author></authors></contributors><auth-address>Cancer Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010, Australia. mrobinson@wehi.edu.au</auth-address><titles><title>edgeR: a Bioconductor package for differential expression analysis of digital gene expression data</title><secondary-title>Bioinformatics</secondary-title></titles><periodical><full-title>Bioinformatics</full-title></periodical><pages>139-40</pages><volume>26</volume><number>1</number><keywords><keyword>*Algorithms</keyword><keyword>Gene Expression Profiling/*methods</keyword><keyword>Oligonucleotide Array Sequence Analysis/*methods</keyword><keyword>*Programming Languages</keyword><keyword>*Signal Processing, Computer-Assisted</keyword><keyword>*Software</keyword></keywords><dates><year>2010</year><pub-dates><date>Jan 01</date></pub-dates></dates><isbn>1367-4811 (Electronic)
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ADDIN EN.CITE.DATA 16 with genes passing differential expression analysis (FDR < 0.25) and pre-ranked by log(fold change in transcript counts), and the gene sets database h.all.v5.2.symbols.gmt [Hallmarks].Microarray Microarray services were provided by the UPENN Molecular Profiling Facility, including quality control tests of the total RNA samples by Agilent Bioanalyzer and Nanodrop spectrophotometry. All protocols were conducted as described in the Affymetrix WT Plus Reagent Kit Manual and the Affymetrix GeneChip Expression Analysis Technical Manual. Briefly, 250ng of total RNA was converted to first-strand cDNA using reverse transcriptase primed by poly(T) and random oligomers that incorporated the T7 promoter sequence. Second-strand cDNA synthesis was followed by in vitro transcription with T7 RNA polymerase for linear amplification of each transcript, and the resulting cRNA was converted to cDNA, fragmented, assessed by Bioanalyzer, and biotinylated by terminal transferase end labeling. Five and a half micrograms of labeled cDNA were added to Affymetrix hybridization cocktails, heated at 99?C for 5 min and hybridized for 16 h at 45?C to Mouse Transcriptome 1.0 ST GeneChips (Affymetrix Inc., Santa Clara CA) using the GeneChip Hybridization oven 645. The microarrays were then washed at low (6X SSPE) and high (100mM MES, 0.1M NaCl) stringency and stained with streptavidin-phycoerythrin. Fluorescence was amplified by adding biotinylated anti-streptavidin and an additional aliquot of streptavidin-phycoerythrin stain. A GeneChip 3000 7G scanner was used to collect fluorescence signal. Affymetrix Command Console and Expression Console were used to quantitate expression levels for targeted genes; default values provided by Affymetrix were applied to all analysis parameters. Affymetrix cel (probe intensity) files were normalized and summarized using RMA-SST to the gene level using Expression Console software (v1.4.1). Inter sample variation was visualized using Principal Components Analysis in Partek Genomics Suite (v6.6, Partek, Inc., St. Louis, MO). Cell Trace. CellTrace far red cell proliferation kit for flow cytometry (Thermo Fisher Scientific). GFP-WT-AMOT and pcdh-EF1-GFP vector were transduced into the HT-1080 cells. Through cell sorting, GFP positive cells were harvested and plated in 6cm dishes. After incubation overnight, cultured cells were labeled with CellTrace far red solution for 20 mins. Then cell trace solution was removed and cells were washed twice, and replaced with fresh pre-warmed complete culture medium. Fluorescently labeled cells were monitored under the microscope (Wide field Olympus Ix81) at day1 and day 5. After cells were incubated for 5 days, samples were harvested and washed once with MACS buffer. Cells were analyzed by LSRII (BD, Bioscience) flow cytometer and results analyzed using the FlowJo 7.6 software.Immunoprecipitation and Immunofluorescence. HT-1080 cells were treated with SAHA 2?M and JQ1 0.5?M 24hrs. Then cells were harvested and resuspended in 1% CHAPS lysis buffer with protease inhibitors (Thermo Fisher Scientific). 6% supernatant of sample was used for input. Endogenous IPs were performed by using Dynabeads M280 sheep anti-rabbit (Thermo Fisher Scientific). Beads and lysate were incubated overnight with rocking at 4oC. Beads were washed, and then boiling with loading buffer for 5 min. The sample was removed from the beads by magnetic separation and then run on an 8% (vol/vol) SDS/PAGE gel for immunoblot analysis. The following primary antibodies were used: rabbit anti-AMOT (43130; 1:500), rabbit anti-YAP1 (4912; 1:200) (Cell Signaling Technology). The following primary antibodies and regents were used for immunofluorescence: rabbit anti-YAP (H-125) (15407; 1:100) (Santa Cruz). Alexa Fluor 488 Phalloidin (8878; Cell Signaling Technology). Mounting medium with DAPI (P36971; Thermo Fisher Scientific) was applied last. Slides were imaged using a Nikon microscope Eclipse series scope. Proliferation Assays. MTT. 3,000 (HT-1080 and KP230) or 1,000 KIA cells/well in 96-well plates containing titrations and or combination compounds as indicated dose of SAHA and JQ1 and maintained for 72hrs at 37?C with 5% CO2. 50ul of MTT [3-(4,5-dimethylthiazol-2,5-diphenyl) tetrazolium bromide; 2 mg/ml, Sigma-Aldrich] was added to the culture medium of growing cells at the indicated time points and the cells were incubated for a further 2 hrs. Dimethylsufoxide (DMSO 200 μl/well, Corning) was added and absorbance was measured at 570 nm using a model SpectraMax Microplate Reader. Cell Counting. For shRNA studies, cells were incubated with lentivirus for 48h and then trypsinized and replated followed by daily counting for 4-5 days. Drugs were replenished every 24 hrs.Annexin V/PI Staining. 150,000 HT-1080 cells were plated per 6cm dish. Cells were incubated overnight and then treated with 2 ?M SAHA and 0.5 ?M JQ1 for 48 hrs. Six hours prior to harvest of cells, we treated positive control plates with 1?M Staurosporin to induce apoptosis. We washed the cells twice with cold PBS, centrifuged at 1000 rpm for 5 min, resuspended each sample pellet in 100ul 1x staining solution with 5 ?L Annexin and 5 ?L PI (556547, BD). Incubate cells in the dark for 15 min at room temperature, vortexing every 5 min. Then add 240 ?L of 1x Binding Buffer and cells were analyzed by LSRII flow cytometer (BD, Bioscience). The percentage of viable cells (low annexin V-FITC/Low PI-PE), early apoptotic cells (high annexin V-FITC/PI-PE), and late apoptotic/necrotic cells (high annexin V-FITC/high PI-PE) was determined.BrdU Assay. To evaluate whether SAHA/JQ1 and Caffeic Acid Phenethyl Ester (CAPE, Selleckchem) alter the cell cycle, FITC BrdU Flow Kits were purchased from BD Pharmingen? (San Jose, CA). According to manufacturer’s protocol, after HT-1080 cells treated with SAHA (2?M)/JQ1 (0.5?M) or CAPE (15?M) 44.5 hrs, cells were labeled with Bromodeoxyuridine (BrdU) 3.5 hrs. Cultured cells were harvested by trypsinization and then were fixed and permeabilized with BD Cytofix/Cytoperm Buffer. Following Fixation, cells were treated with DNase for 1 hr to expose incorporated BrdU. The incorporated BrdU is stained with specific anti-BrdU fluorescent antibody FITC (530/30 Blue-A) 20 mins. After washing the cells in 1xBD Perm/Wash, total DNA was stained using 7AAD (670LP Blue-A) solution. The stained cells were analyzed by LSRII flow cytometer (BD Biosciences) and results analyzed using the FlowJo 7.6 software.qRT-PCR. Total RNA was isolated from tissues and cell using the TRIzol regent (Life Technologies) and RNeasy Mini Kit (Qiagen). Reverse transcription of mRNA was performed using the High-Capacity RNA-to-cDNA Kit (Life Technologies). qRT-PCR was performed by using a ViiA7 apparatus. All probes were obtained from TaqMan" best coverage" (Life Technologies). HPRT and SDH1 were used as endogenous controls. Transient Transfections. Myc dsiRNA (HSC.RNAI.N002467: 12.1, 12.2, 12.3) were obtained from Integrated DNA Technologies. SMARTpool: ON-TARGETplus Cdkn1c siRNA and Myod1 siRNA and Non-targeting siRNA were purchased from Dharmacon.Supplemental Figure legendsSupplemental Figure 1. (A) Diagnostic details of patient biopsy cores from USBiomax tissue microarray slide SO801a (The classification “MFH” is antiquated and has now been replaced with “UPS”). (B) Quantification of IHC Images of tumor tissues from KP and KPY for Yap SEM; P=0.0003 and (C) Ki67 SEM; P=0.002 Supplemental Figure 2. (A) Genome track of ChIP-seq signals in units of rpm/bp for H3K27ac at whole genome from primary human UPS samples, including two freshly obtained sample and one obtained from tissue bank. Box plot of NF-κB associated SE compared to all SE. (B) Gene tracks of control input ChIP-seq signals in units of rpm/bp at the RELA, (C) BCL3 and (D) RELB regions, the three signature regions for NF-κB pathway, with no H3K27Ac signal. (E) Higher resolution view of NF-κB targets upregulated in human UPS tumors compared to muscle from RNA-seq analysis and volcano plot in Figure 2J. (F) GSEA of gene expression changes from human UPS sample #1 compared with normal human skeletal muscle tissue. Pathway analysis was performed with genes passing differential expression analysis (FDR < 0.25) and pre-ranked by logFC.Supplemental Figure 3. (A) Proliferation assay of KP, HT-1080 and KIA cells treated with JQ1 in a dose dependent manner, SD; All *P<0.05, (multiple stars address all the lines below them) (B) Western blot quantification of Yap1 from 5 independent DMSO and JQ1 tumors. One outlier (red circle) was identified and removed from the statistical analysis. SEM; P=0.046 (C) Proliferation assay of KP cells treated with YAPS6A and WT-YAP with or without 250nM JQ1, SEM; *P<0.05. (D) Western blot of V5-YAPS6A and V5-WT-YAP from DMSO and 250nM JQ1 group. (E) qRT-PCR analysis of HT-1080 treated with 250 nM and 500 nM JQ1 for 24hrs shows that JQ1 treatment decreased mRNA levels of YAP1, SD; All *P<0.05. (F) qRT-PCR analysis of HT-1080, KIA and KP with 500nM JQ1 at 48hrs show that JQ1 treatment decreased mRNA levels of YAP1 SD; All *P<0.02, assays performed in triplicate) Supplemental Figure 4. (A) Western blot of HT-1080, KIA, KP cells treated with 0.5mM JQ1 for YAP1 and MYC. (B) Proliferation analysis of HT-1080 cells treated with MYC dsiRNA (n=3), SD NS. (C) Western blot of MYC and YAP in HT-1080 cells after silencing MYC by dsiRNA 48hrs. (D) Kaplan-Meier curve of overall survival of UPS patients divided into high, medium, and low MYC expression from the TCGA sarcoma dataset (N=29). (E) 72hr MTT proliferation assay of HT-1080 cells treated with SAHA and JQ1 as indicated. Dose response shows that combination treatment is more effective. SEM; All *P<0.0002, n=3. (F) Western blot of YAP and FOXM1 from STS109, RD, LPS863, LPS224, SKLMS1, and SKUT1 treated with SAHA (2?M), JQ1 (0.5?M) or both in vitro for 48hrs. (G) Western blot of LATS1, MST1 and (H) MST2 in KP cells treated with SAHA (2?M)/JQ1 (0.5?M) 24hrs using Phospho-Tag gel.Supplemental Figure 5. (A) Western blot of P-Yap1 and Yap1 in KP cells treated with SAHA/JQ1 for 24 hrs. (B) Western blot of P-Yap1, Yap1, HSP90 and LAMB from fractionated KP cells treated with SAHA/JQ1 in a time dependent manner.Supplemental Figure 6. (A) AMOT mRNA levels in normal tissues including skeletal muscle (teal bar) as well as many sarcoma subtypes including different lipoarcomas (LS), Leiomyosarcomas (LMS), Fibrosarcomas (FS) and UPS. (B) Western blot of P-YAP1 and YAP1 in KP cells after treated with XAV939 (Tankyrase inhibitor) 48hrs on dose dependent manner. (C) Images and sorting purity from control and WT-GFP-AMOT transduced HT-1080 before and after cell sorting. (D) Images captured at day 1 and day 5 after transduced cells loaded with CellTrace dye. (E) Flow cytometry quantification of CellTrace positive cells after 5 days culture. GFP-AMOT positive cells contained 50% more CellTrace than control cells indicating that these cells are significantly less proliferative. (n=3). SD; *P=0.0004 (F) Flow cytometry quantification of remaining GFP+ cells after 5 days in culture; n=3. SD; *P=0.005Supplemental Figure 7. (A) IPA of KP/KPY microarray discussed in Figure 1. Reflects pathway changes present in KPY tumors. (B) Western blot of Caspase 3, Cleaved Caspase 3 and YAP from KP cells treated in vitro with SAHA (2?M)/JQ1 (0.5?M) or 1?M Staurosporin for 48hrs. ADDIN EN.REFLIST References1Langmead, B., Trapnell, C., Pop, M. & Salzberg, S. L. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome biology 10, doi:10.1186/gb-2009-10-3-r25 (2009).2Zhang, Y. et al. Model-based analysis of ChIP-Seq (MACS). Genome biology 9, doi:10.1186/gb-2008-9-9-r137 (2008).3Brown, J. D. et al. NF-κB Directs Dynamic Super Enhancer Formation in Inflammation and Atherogenesis. Molecular Cell 56, 219-231, doi:10.1016/j.molcel.2014.08.024 (2014).4Lin, C. Y. et al. Transcriptional amplification in tumor cells with elevated c-Myc. 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