Person: Padi, Megha
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Padi
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Megha
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Padi, Megha
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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 Integrating transcriptional and protein interaction networks to prioritize condition-specific master regulators(BioMed Central, 2015) Padi, Megha; Quackenbush, JohnBackground: Genome-wide libraries of yeast deletion strains have been used to screen for genes that drive phenotypes such as stress response. A surprising observation emerging from these studies is that the genes with the largest changes in mRNA expression during a state transition are not those that drive that transition. Here, we show that integrating gene expression data with context-independent protein interaction networks can help prioritize master regulators that drive biological phenotypes. Results: Genes essential for survival had previously been shown to exhibit high centrality in protein interaction networks. However, the set of genes that drive growth in any specific condition is highly context-dependent. We inferred regulatory networks from gene expression data and transcription factor binding motifs in Saccharomyces cerevisiae, and found that high-degree nodes in regulatory networks are enriched for transcription factors that drive the corresponding phenotypes. We then found that using a metric combining protein interaction and transcriptional networks improved the enrichment for drivers in many of the contexts we examined. We applied this principle to a dataset of gene expression in normal human fibroblasts expressing a panel of viral oncogenes. We integrated regulatory interactions inferred from this data with a database of yeast two-hybrid protein interactions and ranked 571 human transcription factors by their combined network score. The ranked list was significantly enriched in known cancer genes that could not be found by standard differential expression or enrichment analyses. Conclusions: There has been increasing recognition that network-based approaches can provide insight into critical cellular elements that help define phenotypic state. Our analysis suggests that no one network, based on a single data type, captures the full spectrum of interactions. Greater insight can instead be gained by exploring multiple independent networks and by choosing an appropriate metric on each network. Moreover we can improve our ability to rank phenotypic drivers by combining the information from individual networks. We propose that such integrative network analysis could be used to combine clinical gene expression data with interaction databases to prioritize patient- and disease-specific therapeutic targets. Electronic supplementary material The online version of this article (doi:10.1186/s12918-015-0228-1) contains supplementary material, which is available to authorized users.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 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 Warped \(AdS_3\) Black Holes(Institute of Physics, 2009) Anninos, Dionysios; Li, Wei; Padi, Megha; Song, Wei; Strominger, AndrewThree dimensional topologically massive gravity (TMG) with a negative cosmological constant \(-\ell^{-2}\) and positive Newton constant \(G\) admits an \(AdS_3\) vacuum solution for any value of the graviton mass \(\mu\). These are all known to be perturbatively unstable except at the recently explored chiral point \(\mu\ell = 1\). However we show herein that for every value of \(\mu\ell \not= 3\) there are two other (potentially stable) vacuum solutions given by \(SL(2,\Re) \times U(1)\)-invariant warped \(AdS_3\) geometries, with a timelike or spacelike \(U(1)\) isometry. Critical behavior occurs at \(\mu\ell = 3\), where the warping transitions from a stretching to a squashing, and there are a pair of warped solutions with a null \(U(1)\) isometry. For \(\mu\ell > 3\), there are known warped black hole solutions which are asymptotic to warped \(AdS_3\). We show that these black holes are discrete quotients of warped \(AdS_3\) just as BTZ black holes are discrete quotients of ordinary \(AdS_3\). Moreover new solutions of this type, relevant to any theory with warped \(AdS_3\) solutions, are exhibited. Finally we note that the black hole thermodynamics is consistent with the hypothesis that, for \(\mu\ell > 3\), the warped \(AdS_3\) ground state of TMG is holographically dual to a 2D boundary CFT with central charges \(c_R = \frac{15(\mu\ell)^2 + 81}{G\mu((\mu\ell)^2 + 27)}\) and \(c_L = \frac{12\mu\ell^2}{G((\mu\ell)^2 + 27)}\).Publication Orientiholes(Springer, 2010) Denef, Frederik; Esole, Mboyo; Padi, MeghaBy T-dualizing space-filling D-branes in 4d IIB orientifold compactifications along the three non-internal spatial directions, we obtain black hole bound states living in a universe with a gauged spatial reflection symmetry. We call these objects orientiholes. The gravitational entropy of various IIA orientihole configurations provides an “experimental” estimate of the number of vacua in various sectors of the IIB landscape. Furthermore, basic physical properties of orientiholes map to (sometimes subtle) microscopic features, thus providing a useful alternative viewpoint on a number of issues arising in D-brane model building. More generally, we give orientihole generalizations of recently derived wall crossing formulae, and conjecture a relation to the topological string analogous to the OSV conjecture, but with a linear rather than a quadratic identification of partition functions.Publication Merkel cell polyomavirus recruits MYCL to the EP400 complex to promote oncogenesis(Public Library of Science, 2017) Cheng, Jingwei; Park, Donglim; Berrios, Christian; White, Elizabeth A.; Arora, Reety; Yoon, Rosa; Branigan, Timothy; Xiao, Tengfei; Westerling, Thomas; Federation, Alexander; Zeid, Rhamy; Strober, Benjamin; Swanson, Selene K.; Florens, Laurence; Bradner, James E; Brown, Myles; Howley, Peter; Padi, Megha; Washburn, Michael P.; DeCaprio, JamesMerkel cell carcinoma (MCC) frequently contains integrated copies of Merkel cell polyomavirus DNA that express a truncated form of Large T antigen (LT) and an intact Small T antigen (ST). While LT binds RB and inactivates its tumor suppressor function, it is less clear how ST contributes to MCC tumorigenesis. Here we show that ST binds specifically to the MYC homolog MYCL (L-MYC) and recruits it to the 15-component EP400 histone acetyltransferase and chromatin remodeling complex. We performed a large-scale immunoprecipitation for ST and identified co-precipitating proteins by mass spectrometry. In addition to protein phosphatase 2A (PP2A) subunits, we identified MYCL and its heterodimeric partner MAX plus the EP400 complex. Immunoprecipitation for MAX and EP400 complex components confirmed their association with ST. We determined that the ST-MYCL-EP400 complex binds together to specific gene promoters and activates their expression by integrating chromatin immunoprecipitation with sequencing (ChIP-seq) and RNA-seq. MYCL and EP400 were required for maintenance of cell viability and cooperated with ST to promote gene expression in MCC cell lines. A genome-wide CRISPR-Cas9 screen confirmed the requirement for MYCL and EP400 in MCPyV-positive MCC cell lines. We demonstrate that ST can activate gene expression in a EP400 and MYCL dependent manner and this activity contributes to cellular transformation and generation of induced pluripotent stem cells.