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  Ernesto GUCCIONE  
  Lab Location: #3-06

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  Key Publications  

MDM4 exon6-inclusion is a widespread oncogenic mechanism and therapeutic target
Michael Dewaele*, Tommaso Tabaglio* , Karen Willekens* , Marco Bezzi*, Shun Xie Teo, Diana HP Low, Cheryl M Koh, […..] Jean-Christophe Marine# and Ernesto Guccione#
J Clin Invest., 2016 Jan #Corresponding Authors

Transcription and Imprinting Dynamics in Developing Postnatal Male Germline Stem Cells
Saher Sue Hammoud, Diana HP Low, Chongil Yi, Chee Leng Lee, Jon Oatley,
Christopher J. Payne, Douglas T. Carrell, Ernesto Guccione# and Bradley R. Cairns#
Genes Dev., 2015 Nov #Corresponding Authors

Regulation of the core pre-mRNA splicing machinery by MYC is essential to sustain lymphomagenesis
Cheryl M Koh*, Marco Bezzi*, Diana HP Low, Wei Xia Ang, Shun Xie Teo, Florence PH Gay, Muthafar Al-Haddawi, Soo Yong Tan, Motomi Osato, Arianna Sabò, Bruno Amati, Keng Boon Wee and Ernesto Guccione
Nature, 2015 Jul 2;523(7558):96-100

Telomerase subunit TERT regulates MYC dependent oncogenesis independent of its reverse transcriptase activity and role on telomeres
Cheryl M Koh*, Ekta Khattar*, Shi Chi Leow, Chia Yi Liu, Julius Muller, Wei Xia Ang, Yinghui Li, Guido Franzoso, Shang Li, Ernesto Guccione# and Vinay Tergaonkar#
J Clin Invest., 2015 May;125(5):2109-22. #Corresponding Authors

Selective transcriptional regulation by Myc in cellular growth control and lymphomagenesis.
Sabò A, Kress TR, Pelizzola M, de Pretis S, Gorski MM, Tesi A, Morelli MJ, Bora P, Doni M,
Verrecchia A, Tonelli C, Fagà G, Bianchi V, Ronchi A, Low D, Müller H, Guccione E, Campaner S, Amati B
Nature, 2014 Jul 24;511(7510):488-92. Epub 2014 Jul 9.

Chromatin and transcription transitions of Mammalian adult germline stem cells and spermatogenesis.
Hammoud SS, Low DH, Yi C, Carrell DT, Guccione E#, Cairns BR#
Cell Stem Cell, 2014 Aug 7;15(2):239-53 #Corresponding Authors

Single-Cell Profiling of Epigenetic Modifiers Identifies PRDM14 as an Inducer of Cell Fate in the Mammalian Embryo
Burton A*, Muller J*, Tu S, Padilla-Longoria P, Guccione E#, Torres-Padilla ME#
Cell Rep., 2013 Nov 14;5(3):687-701. #Corresponding Authors

Regulation of constitutive and alternative splicing by PRMT5 reveals a role for Mdm4 pre-mRNA in sensing defects in the spliceosomal machinery
Bezzi M, Teo SX, Muller J, Mok WC, Sahu SK, Vardy LA, Bonday ZQ, Guccione E
Genes Dev., 2013 Sep 1;27(17):1903-16

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    Ernesto GUCCIONE

Ernesto Guccione obtained his Master's degree in Medical Biotechnology in 2000 from Bologna University and his PhD in 2004 from the International Center for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy. He did his postdoctoral work at the European Institute of Oncology (Milan, Italy) where he studied the role of chromatin in defining c-Myc target site recognition. He also identified PRMT6, a member of the Protein Arginine MethylTransferase family, as an important enzyme in controlling transcriptional repression. During his postdoctoral training, he spent four months as an EMBO fellow in the laboratory of J.LaBaer at Harvard Institute of Proteomics. He joined IMCB in 2008 as an Assistant Professor.

    Methyltransferases in Development and Disease

Our group has a long-term interest in the function of Methyltransferases in Development and Disease.
In the lab we use a combination of approaches to study the function of Protein Arginine MethylTransferases (PRMTs) and PRDI-BF1-RIZ-homology-domain proteins (PRDMs) (Fig.1) in transcriptional and post-transcriptional regulation during development and cancer:

1. Functional screens and Target Identification and Validation:
Loss-of-function (LOF) genetic screens, using pooled shRNA libraries (Bric et al., 2009; Gargiulo et al., 2013; Kaelin, 2009; Lin et al., 2012; Mills et al., 2013; Prahallad et al., 2012), CRISPR/Cas9 libraries (Cong et al., 2013), or arrayed RNAi libraries (Chia et al., 2010) can be successfully exploited to identify genes that drive or inhibit development, cell differentiation or tumorigenesis. We believe that phenotype-driven forward genetic screens are the ideal approach to identify novel biomarkers for therapeutic decisions as well as direct targets for intervention (druggable members of the methyltransferase family of enzymes) (Richon et al., 2011) for the cure of a variety of human cancers or to instruct cell type specification.

2. Conditional Transgenic Knockout (KO) mice: Once we identify direct targets for intervention, we next aim to understand the effect of their depletion in vivo during development and tumorigenesis. To study the former, several projects in the lab have taken advantage of lineage specific deleter-strains to study deletions of selected methyltransferases in different tissues (Testis and Brain among others). For the cancer related projects we mainly take advantage of tumor-prone models such as the Eμ-Myc lymphoma model (Schmitt et al., 1999), which overexpresses the oncogenic transcription factor Myc (Guccione et al., 2006) (Martinato et al., 2008) (Guccione et al., 2007).

3. Biochemistry: All our projects aim at dissecting the biochemical mechanisms driving the in vivo phenotypes we observe upon depletion of the selected methyltransferases. We use in vitro methylation-assays, cell fractionation, in vitro protein-protein interactions and SILAC based quantitative Mass Spectrometry (Migliori et al., 2012) to answer a variety of questions.

4. Bioinformatics: a fundamental part of the work done in the lab deals with large datasets deriving from Chip-Sequencing profiles (of Transcription Factors/co-factors or Histone Post Translational Modifications), DNA methylation landscapes or RNA-Sequencing profiles of wild type or PRMT/PRDM depleted cells or tissues. We also actively collaborate with other groups both internationally and within IMCB, providing our expertise in computational biology (Beillard et al., 2012; Filipponi et al., 2013; Jachowicz et al., 2013; Tsai et al., 2013; Wang et al., 2014).