Person: Morris, Robert
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Morris
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Morris, Robert
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Publication SETD1A modulates cell cycle progression through a miRNA network that regulates p53 target genes(Nature Pub. Group, 2015) Tajima, Ken; Yae, Toshifumi; Javaid, Sarah; Tam, Oliver; Comaills, Valentine; Morris, Robert; Wittner, Ben; Liu, Mingzhu; Engstrom, Amanda; Takahashi, Fumiyuki; Black, Joshua C.; Ramaswamy, Sridhar; Shioda, Toshihiro; Hammell, Molly; Haber, Daniel; Whetstine, Johnathan; Maheswaran, ShyamalaExpression of the p53-inducible antiproliferative gene BTG2 is suppressed in many cancers in the absence of inactivating gene mutations, suggesting alternative mechanisms of silencing. Using a shRNA screen targeting 43 histone lysine methyltransferases (KMTs), we show that SETD1A suppresses BTG2 expression through its induction of several BTG2-targeting miRNAs. This indirect but highly specific mechanism, by which a chromatin regulator that mediates transcriptional activating marks can lead to the downregulation of a critical effector gene, is shared with multiple genes in the p53 pathway. Through such miRNA-dependent effects, SETD1A regulates cell cycle progression in vitro and modulates tumorigenesis in mouse xenograft models. Together, these observations help explain the remarkably specific genetic consequences associated with alterations in generic chromatin modulators in cancer.Publication dREAM co-operates with insulator-binding proteins and regulates expression at divergently paired genes(Oxford University Press, 2014) Korenjak, Michael; Kwon, Eunjeong; Morris, Robert; Anderssen, Endre; Amzallag, Arnaud; Ramaswamy, Sridhar; Dyson, NicholasdREAM complexes represent the predominant form of E2F/RBF repressor complexes in Drosophila. dREAM associates with thousands of sites in the fly genome but its mechanism of action is unknown. To understand the genomic context in which dREAM acts we examined the distribution and localization of Drosophila E2F and dREAM proteins. Here we report a striking and unexpected overlap between dE2F2/dREAM sites and binding sites for the insulator-binding proteins CP190 and Beaf-32. Genetic assays show that these components functionally co-operate and chromatin immunoprecipitation experiments on mutant animals demonstrate that dE2F2 is important for association of CP190 with chromatin. dE2F2/dREAM binding sites are enriched at divergently transcribed genes, and the majority of genes upregulated by dE2F2 depletion represent the repressed half of a differentially expressed, divergently transcribed pair of genes. Analysis of mutant animals confirms that dREAM and CP190 are similarly required for transcriptional integrity at these gene pairs and suggest that dREAM functions in concert with CP190 to establish boundaries between repressed/activated genes. Consistent with the idea that dREAM co-operates with insulator-binding proteins, genomic regions bound by dREAM possess enhancer-blocking activity that depends on multiple dREAM components. These findings suggest that dREAM functions in the organization of transcriptional domains.Publication Neural processes underlying self- and other-related lies: An individual difference approach using fMRI(Informa UK Limited, 2009) Ganis, Giorgio; Morris, Robert; Kosslyn, StephenTwo hypotheses were tested using a novel individual differences approach, which identifies rate-limiting brain regions, that is, brain regions in which variations in neural activity predict variations in behavioral performance. The first hypothesis is that the rate-limiting regions that support the production of lies about oneself (self-related) are partially distinct from those underlying the production of lies about other individuals (other-related). The second hypothesis is that a cingulate!insular!prefrontal network found to be rate-limiting for interference tasks is involved in both types of lies. The results confirmed both hypotheses and supported the utility of this individual differences approach in the study of deception in particular, as well in the study of complex cognitive phenomena more generallyPublication Expression of β-globin by cancer cells promotes cell survival during blood-borne dissemination(Nature Publishing Group, 2017) Zheng, Yu; Miyamoto, David; Wittner, Ben; Sullivan, James; Aceto, Nicola; Jordan, Nicole Vincent; Yu, Min; Karabacak, Nezihi; Comaills, Valentine; Morris, Robert; Desai, Rushil; Desai, Niyati; Emmons, Erin; Milner, John D.; Lee, Richard; Wu, Chin-Lee; Sequist, Lecia; Haas, Wilhelm; Ting, David; Toner, Mehmet; Ramaswamy, Sridhar; Maheswaran, Shyamala; Haber, DanielMetastasis-competent circulating tumour cells (CTCs) experience oxidative stress in the bloodstream, but their survival mechanisms are not well defined. Here, comparing single-cell RNA-Seq profiles of CTCs from breast, prostate and lung cancers, we observe consistent induction of β-globin (HBB), but not its partner α-globin (HBA). The tumour-specific origin of HBB is confirmed by sequence polymorphisms within human xenograft-derived CTCs in mouse models. Increased intracellular reactive oxygen species (ROS) in cultured breast CTCs triggers HBB induction, mediated through the transcriptional regulator KLF4. Depletion of HBB in CTC-derived cultures has minimal effects on primary tumour growth, but it greatly increases apoptosis following ROS exposure, and dramatically reduces CTC-derived lung metastases. These effects are reversed by the anti-oxidant N-Acetyl Cysteine. Conversely, overexpression of HBB is sufficient to suppress intracellular ROS within CTCs. Altogether, these observations suggest that β-globin is selectively deregulated in cancer cells, mediating a cytoprotective effect during blood-borne metastasis.Publication Detection of Dysregulated Protein Association Networks by High-Throughput Proteomics Predicts Cancer Vulnerabilities(2017) Lapek, John D.; Greninger, Patricia; Morris, Robert; Amzallag, Arnaud; Pruteanu-Malinici, Iulian; Benes, Cyril; Haas, WilhelmThe formation of protein complexes and the co-regulation of the cellular concentrations of proteins are essential mechanisms for cellular signaling and for maintaining homeostasis. Here we use isobaric labeling multiplexed proteomics to analyze protein co-regulation and show that this allows the identification of protein-protein associations with high accuracy. We apply this ‘interactome mapping by high-throughput quantitative proteome analysis’ (IMAHP) method to a panel of 41 breast cancer cell lines and show that deviations of the observed protein co-regulations in specific cell lines from the consensus network impacts to cellular fitness. Furthermore, these aberrant interactions serve as biomarkers predicting drug sensitivity of cell lines in screens across 195 drugs. We expect that IMAHP can be broadly used to gain insight into how changing landscapes of protein-protein associations affect the phenotype of biological systems.