Person: DeCaprio, James
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DeCaprio
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James
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DeCaprio, James
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Publication Proteomic Landscape of Tissue-Specific Cyclin E Functions in Vivo(Public Library of Science, 2016) Odajima, Junko; Saini, Siddharth; Jung, Piotr; Ndassa-Colday, Yasmine; Ficaro, Scott; Geng, Yan; Marco, Eugenio; Michowski, Wojciech; Wang, Yaoyu E.; DeCaprio, James; Litovchick, Larisa; Marto, Jarrod; Sicinski, PiotrE-type cyclins (cyclins E1 and E2) are components of the cell cycle machinery that has been conserved from yeast to humans. The major function of E-type cyclins is to drive cell division. It is unknown whether in addition to their ‘core’ cell cycle functions, E-type cyclins also perform unique tissue-specific roles. Here, we applied high-throughput mass spectrometric analyses of mouse organs to define the repertoire of cyclin E protein partners in vivo. We found that cyclin E interacts with distinct sets of proteins in different compartments. These cyclin E interactors are highly enriched for phosphorylation targets of cyclin E and its catalytic partner, the cyclin-dependent kinase 2 (Cdk2). Among cyclin E interactors we identified several novel tissue-specific substrates of cyclin E-Cdk2 kinase. In proliferating compartments, cyclin E-Cdk2 phosphorylates Lin proteins within the DREAM complex. In the testes, cyclin E-Cdk2 phosphorylates Mybl1 and Dmrtc2, two meiotic transcription factors that represent key regulators of spermatogenesis. In embryonic and adult brains cyclin E interacts with proteins involved in neurogenesis, while in adult brains also with proteins regulating microtubule-based processes and microtubule cytoskeleton. We also used quantitative proteomics to demonstrate re-wiring of the cyclin E interactome upon ablation of Cdk2. This approach can be used to study how protein interactome changes during development or in any pathological state such as aging or cancer.Publication Integration of TP53, DREAM, MMB-FOXM1 and RB-E2F target gene analyses identifies cell cycle gene regulatory networks(Oxford University Press, 2016) Fischer, Martin; Grossmann, Patrick; Padi, Megha; DeCaprio, JamesCell cycle (CC) and TP53 regulatory networks are frequently deregulated in cancer. While numerous genome-wide studies of TP53 and CC-regulated genes have been performed, significant variation between studies has made it difficult to assess regulation of any given gene of interest. To overcome the limitation of individual studies, we developed a meta-analysis approach to identify high confidence target genes that reflect their frequency of identification in independent datasets. Gene regulatory networks were generated by comparing differential expression of TP53 and CC-regulated genes with chromatin immunoprecipitation studies for TP53, RB1, E2F, DREAM, B-MYB, FOXM1 and MuvB. RNA-seq data from p21-null cells revealed that gene downregulation by TP53 generally requires p21 (CDKN1A). Genes downregulated by TP53 were also identified as CC genes bound by the DREAM complex. The transcription factors RB, E2F1 and E2F7 bind to a subset of DREAM target genes that function in G1/S of the CC while B-MYB, FOXM1 and MuvB control G2/M gene expression. Our approach yields high confidence ranked target gene maps for TP53, DREAM, MMB-FOXM1 and RB-E2F and enables prediction and distinction of CC regulation. A web-based atlas at www.targetgenereg.org enables assessing the regulation of any human gene of interest.Publication Merkel Cell Polyomavirus Small T Antigen Promotes Pro-Glycolytic Metabolic Perturbations Required for Transformation(Public Library of Science, 2016) Berrios, Christian; Padi, Megha; Keibler, Mark A.; Park, Donglim; Molla, Vadim; Cheng, Jingwei; Lee, Soo Mi; Stephanopoulos, Gregory; Quackenbush, John; DeCaprio, JamesMerkel cell polyomavirus (MCPyV) is an etiological agent of Merkel cell carcinoma (MCC), a highly aggressive skin cancer. The MCPyV small tumor antigen (ST) is required for maintenance of MCC and can transform normal cells. To gain insight into cellular perturbations induced by MCPyV ST, we performed transcriptome analysis of normal human fibroblasts with inducible expression of ST. MCPyV ST dynamically alters the cellular transcriptome with increased levels of glycolytic genes, including the monocarboxylate lactate transporter SLC16A1 (MCT1). Extracellular flux analysis revealed increased lactate export reflecting elevated aerobic glycolysis in ST expressing cells. Inhibition of MCT1 activity suppressed the growth of MCC cell lines and impaired MCPyV-dependent transformation of IMR90 cells. Both NF-κB and MYC have been shown to regulate MCT1 expression. While MYC was required for MCT1 induction, MCPyV-induced MCT1 levels decreased following knockdown of the NF-κB subunit RelA, supporting a synergistic activity between MCPyV and MYC in regulating MCT1 levels. Several MCC lines had high levels of MYCL and MYCN but not MYC. Increased levels of MYCL was more effective than MYC or MYCN in increasing extracellular acidification in MCC cells. Our results demonstrate the effects of MCPyV ST on the cellular transcriptome and reveal that transformation is dependent, at least in part, on elevated aerobic glycolysis.Publication Merkel Cell Polyomavirus Exhibits Dominant Control of the Tumor Genome and Transcriptome in Virus-Associated Merkel Cell Carcinoma(American Society for Microbiology, 2017) Starrett, Gabriel J.; Marcelus, Christina; Cantalupo, Paul G.; Katz, Joshua P.; Cheng, Jingwei; Akagi, Keiko; Thakuria, Manisha; Rabinowits, Guilherme; Wang, Linda C.; Symer, David E.; Pipas, James M.; Harris, Reuben S.; DeCaprio, JamesABSTRACT Merkel cell polyomavirus is the primary etiological agent of the aggressive skin cancer Merkel cell carcinoma (MCC). Recent studies have revealed that UV radiation is the primary mechanism for somatic mutagenesis in nonviral forms of MCC. Here, we analyze the whole transcriptomes and genomes of primary MCC tumors. Our study reveals that virus-associated tumors have minimally altered genomes compared to non-virus-associated tumors, which are dominated by UV-mediated mutations. Although virus-associated tumors contain relatively small mutation burdens, they exhibit a distinct mutation signature with observable transcriptionally biased kataegic events. In addition, viral integration sites overlap focal genome amplifications in virus-associated tumors, suggesting a potential mechanism for these events. Collectively, our studies indicate that Merkel cell polyomavirus is capable of hijacking cellular processes and driving tumorigenesis to the same severity as tens of thousands of somatic genome alterations.Publication Interpreting Cancer Genomes Using Systematic Host Perturbations by Tumour Virus Proteins(Nature Publishing Group, 2012) Rozenblatt-Rosen, Orit; Deo, Rahul C.; Dricot, Amélie; Askenazi, Manor; Tavares, Maria; Abderazzaq, Fieda; Byrdsong, Danielle; Correll, Mick; Fan, Changyu; Feltkamp, Mariet C.; Franchi, Rachel; Garg, Brijesh K.; Gulbahce, Natali; Hao, Tong; Korkhin, Anna; Litovchick, Larisa; Mar, Jessica C.; Pak, Theodore R.; Rabello, Sabrina; Rubio, Renee; Shen, Yun; Tasan, Murat; Wanamaker, Shelly; Roecklein-Canfield, Jennifer; Johannsen, Eric; Barabási, Albert-László; Padi, Megha; Adelmant, Guillaume; Calderwood, Michael; Rolland, Thomas; Grace, Miranda; Pevzner, Samuel; Carvunis, Anne-Ruxandra; Chen, Alyce; Cheng, Jingwei; Duarte, Melissa; Ficarro, Scott; Holthaus, Amy Marie; James, Robert; Singh, Saurav; Spangle, Jennifer; Webber, James T.; Beroukhim, Rameen; Kieff, Elliott; Cusick, Michael; Hill, David; Munger, Karl; Marto, Jarrod; Quackenbush, John; Roth, Fritz; DeCaprio, James; Vidal, MarcGenotypic differences greatly influence susceptibility and resistance to disease. Understanding genotype-phenotype relationships requires that phenotypes be viewed as manifestations of network properties, rather than simply as the result of individual genomic variations. Genome sequencing efforts have identified numerous germline mutations associated with cancer predisposition and large numbers of somatic genomic alterations. However, it remains challenging to distinguish between background, or “passenger” and causal, or “driver” cancer mutations in these datasets. Human viruses intrinsically depend on their host cell during the course of infection and can elicit pathological phenotypes similar to those arising from mutations. To test the hypothesis that genomic variations and tumour viruses may cause cancer via related mechanisms, we systematically examined host interactome and transcriptome network perturbations caused by DNA tumour virus proteins. The resulting integrated viral perturbation data reflects rewiring of the host cell networks, and highlights pathways that go awry in cancer, such as Notch signalling and apoptosis. We show that systematic analyses of host targets of viral proteins can identify cancer genes with a success rate on par with their identification through functional genomics and large-scale cataloguing of tumour mutations. Together, these complementary approaches result in increased specificity for cancer gene identification. Combining systems-level studies of pathogen-encoded gene products with genomic approaches will facilitate prioritization of cancer-causing driver genes so as to advance understanding of the genetic basis of human cancer.Publication Identification of FAM111A as an SV40 Host Range Restriction and Adenovirus Helper Factor(Public Library of Science, 2012) Fine, Debrah A.; Rozenblatt-Rosen, Orit; Padi, Megha; Korkhin, Anna; James, Robert L.; Adelmant, Guillaume; Yoon, Rosa; Guo, Luxuan; Berrios, Christian Jose; Zhang, Ying; Calderwood, Michael; Velmurgan, Soundarapandian; Cheng, Jingwei; Marto, Jarrod; Hill, David; Cusick, Michael; Vidal, Marc; Florens, Laurence; Washburn, Michael P.; Litovchick, Larisa; DeCaprio, JamesThe small genome of polyomaviruses encodes a limited number of proteins that are highly dependent on interactions with host cell proteins for efficient viral replication. The SV40 large T antigen (LT) contains several discrete functional domains including the LXCXE or RB-binding motif, the DNA binding and helicase domains that contribute to the viral life cycle. In addition, the LT C-terminal region contains the host range and adenovirus helper functions required for lytic infection in certain restrictive cell types. To understand how LT affects the host cell to facilitate viral replication, we expressed full-length or functional domains of LT in cells, identified interacting host proteins and carried out expression profiling. LT perturbed the expression of p53 target genes and subsets of cell-cycle dependent genes regulated by the DREAM and the B-Myb-MuvB complexes. Affinity purification of LT followed by mass spectrometry revealed a specific interaction between the LT C-terminal region and FAM111A, a previously uncharacterized protein. Depletion of FAM111A recapitulated the effects of heterologous expression of the LT C-terminal region, including increased viral gene expression and lytic infection of SV40 host range mutants and adenovirus replication in restrictive cells. FAM111A functions as a host range restriction factor that is specifically targeted by SV40 LT.Publication Viral Perturbations of Host Networks Reflect Disease Etiology(Public Library of Science, 2012) Gulbahce, Natali; Yan, Han; Dricot, Amélie; Padi, Megha; Byrdsong, Danielle; Franchi, Rachel; Lee, Deok-Sun; Rozenblatt-Rosen, Orit; Mar, Jessica C.; Calderwood, Michael; Baldwin, Amy; Zhao, Bo; Santhanam, Balaji; Braun, Pascal; Simonis, Nicolas; Huh, Kyung-Won; Hellner, Karin; Grace, Miranda; Chen, Alyce; Rubio, Renee; Marto, Jarrod; Christakis, Nicholas A.; Kieff, Elliott; Roth, Fritz; Roecklein-Canfield, Jennifer; DeCaprio, James; Cusick, Michael; Quackenbush, John; Hill, David; Münger, Karl; Vidal, Marc; Barabási, Albert-LászlóMany human diseases, arising from mutations of disease susceptibility genes (genetic diseases), are also associated with viral infections (virally implicated diseases), either in a directly causal manner or by indirect associations. Here we examine whether viral perturbations of host interactome may underlie such virally implicated disease relationships. Using as models two different human viruses, Epstein-Barr virus (EBV) and human papillomavirus (HPV), we find that host targets of viral proteins reside in network proximity to products of disease susceptibility genes. Expression changes in virally implicated disease tissues and comorbidity patterns cluster significantly in the network vicinity of viral targets. The topological proximity found between cellular targets of viral proteins and disease genes was exploited to uncover a novel pathway linking HPV to Fanconi anemia.Publication Does a New Polyomavirus Contribute to Merkel Cell Carcinoma?(BioMed Central, 2008) Garneski, Kelly M; DeCaprio, James; Nghiem, PaulA new technique designed to hunt for non-human transcripts has identified a novel SV40-like virus present in the majority of Merkel cell carcinomas. Here we examine what it will take to determine whether or not this virus contributes to carcinogenesis.Publication The CHR Promoter Element Controls Cell Cycle-Dependent Gene Transcription and Binds the DREAM and MMB Complexes(Oxford University Press, 2011) Müller, Gerd A.; Quaas, Marianne; Schümann, Michael; Krause, Eberhard; Padi, Megha; Fischer, Martin; Litovchick, Larisa; DeCaprio, James; Engeland, KurtCell cycle-dependent gene expression is often controlled on the transcriptional level. Genes like \(cyclin B, CDC2\) and \(CDC25C\) are regulated by cell cycle-dependent element (CDE) and cell cycle genes homology region (CHR) promoter elements mainly through repression in \(G_0/G_1\). It had been suggested that E2F4 binding to CDE sites is central to transcriptional regulation. However, some promoters are only controlled by a CHR. We identify the DREAM complex binding to the CHR of mouse and human \(cyclin B2\) promoters in \(G_0\). Association of DREAM and cell cycle-dependent regulation is abrogated when the CHR is mutated. Although E2f4 is part of the complex, a CDE is not essential but can enhance binding of DREAM. We show that the CHR element is not only necessary for repression of gene transcription in \(G_0/G_1\), but also for activation in S, \(G_2\) and M phases. In proliferating cells, the B-myb-containing MMB complex binds the CHR of both promoters independently of the CDE. Bioinformatic analyses identify many genes which contain conserved CHR elements in promoters binding the DREAM complex. With \(Ube2c\) as an example from that screen, we show that inverse CHR sites are functional promoter elements that can bind DREAM and MMB. Our findings indicate that the CHR is central to DREAM/MMB-dependent transcriptional control during the cell cycle.Publication Merkel Cell Polyomavirus Activates LSD1-Mediated Blockade of Non-Canonical BAF to Regulate Transformation and Tumorigenesis(Springer Science and Business Media LLC, 2020-04-13) Park, Donglim Esther; Cheng, Jingwei; McGrath, John P.; Lim, Matthew Y.; Cushman, Camille; Swanson, Selene K.; Tillgren, Michelle L.; Gokhale, Prafulla C.; Florens, Laurence; Washburn, Michael P.; Trojer, Patrick; Paulo, Joao; DeCaprio, JamesMerkel cell carcinoma (MCC), a neuroendocrine cancer of the skin, is caused by integration of Merkel cell polyomavirus (MCV) and persistent expression of Large T antigen (LT) and Small T antigen (ST). We report that ST in complex with MYCL and the EP400 complex activates expression of LSD1 (KDM1A), RCOR2, and INSM1 to repress gene expression by the lineage transcription factor ATOH1. LSD1 inhibition reduces growth of MCC in vitro and in vivo. Through a forward-genetics CRISPR-Cas9 screen, we identified an antagonistic relationship between LSD1 and the non-canonical BAF (ncBAF) chromatin remodeling complex. Changes in gene expression and chromatin accessibility caused by LSD1 inhibition could be partially rescued by BRD9 inhibition, revealing that LSD1 and ncBAF antagonistically regulate an overlapping set of genes. Our work provides mechanistic insight into the dependence of MCC on LSD1 and a tumor suppressor role for ncBAF in cancer.