Transcriptome Analyses Based on Genetic Screens
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The Master Neural Transcription Factor BRN2 Is an Androgen Receptor–Suppressed Driver of Neuroendocrine Differentiation in Prostate Cancer
Published OnlineFirst October 26, 2016; DOI: 10.1158/2159-8290.CD-15-1263 RESEARCH ARTICLE The Master Neural Transcription Factor BRN2 Is an Androgen Receptor–Suppressed Driver of Neuroendocrine Differentiation in Prostate Cancer Jennifer L. Bishop1, Daksh Thaper1,2, Sepideh Vahid1,2, Alastair Davies1, Kirsi Ketola1, Hidetoshi Kuruma1, Randy Jama1, Ka Mun Nip1,2, Arkhjamil Angeles1, Fraser Johnson1, Alexander W. Wyatt1,2, Ladan Fazli1,2, Martin E. Gleave1,2, Dong Lin1, Mark A. Rubin3, Colin C. Collins1,2, Yuzhuo Wang1,2, Himisha Beltran3, and Amina Zoubeidi1,2 ABSTRACT Mechanisms controlling the emergence of lethal neuroendocrine prostate cancer (NEPC), especially those that are consequences of treatment-induced suppression of the androgen receptor (AR), remain elusive. Using a unique model of AR pathway inhibitor–resistant prostate cancer, we identified AR-dependent control of the neural transcription factor BRN2 (encoded by POU3F2) as a major driver of NEPC and aggressive tumor growth, both in vitro and in vivo. Mecha- nistic studies showed that AR directly suppresses BRN2 transcription, which is required for NEPC, and BRN2-dependent regulation of the NEPC marker SOX2. Underscoring its inverse correlation with clas- sic AR activity in clinical samples, BRN2 expression was highest in NEPC tumors and was significantly increased in castration-resistant prostate cancer compared with adenocarcinoma, especially in patients with low serum PSA. These data reveal a novel mechanism of AR-dependent control of NEPC and suggest that targeting BRN2 is a strategy to treat or prevent neuroendocrine differentiation in prostate tumors. SIGNIFICANCE: Understanding the contribution of the AR to the emergence of highly lethal, drug- resistant NEPC is critical for better implementation of current standard-of-care therapies and novel drug design. -
Core Transcriptional Regulatory Circuitries in Cancer
Oncogene (2020) 39:6633–6646 https://doi.org/10.1038/s41388-020-01459-w REVIEW ARTICLE Core transcriptional regulatory circuitries in cancer 1 1,2,3 1 2 1,4,5 Ye Chen ● Liang Xu ● Ruby Yu-Tong Lin ● Markus Müschen ● H. Phillip Koeffler Received: 14 June 2020 / Revised: 30 August 2020 / Accepted: 4 September 2020 / Published online: 17 September 2020 © The Author(s) 2020. This article is published with open access Abstract Transcription factors (TFs) coordinate the on-and-off states of gene expression typically in a combinatorial fashion. Studies from embryonic stem cells and other cell types have revealed that a clique of self-regulated core TFs control cell identity and cell state. These core TFs form interconnected feed-forward transcriptional loops to establish and reinforce the cell-type- specific gene-expression program; the ensemble of core TFs and their regulatory loops constitutes core transcriptional regulatory circuitry (CRC). Here, we summarize recent progress in computational reconstitution and biologic exploration of CRCs across various human malignancies, and consolidate the strategy and methodology for CRC discovery. We also discuss the genetic basis and therapeutic vulnerability of CRC, and highlight new frontiers and future efforts for the study of CRC in cancer. Knowledge of CRC in cancer is fundamental to understanding cancer-specific transcriptional addiction, and should provide important insight to both pathobiology and therapeutics. 1234567890();,: 1234567890();,: Introduction genes. Till now, one critical goal in biology remains to understand the composition and hierarchy of transcriptional Transcriptional regulation is one of the fundamental mole- regulatory network in each specified cell type/lineage. -
C.V. De Margaret Buckingham, Membre De L'académie Des Sciences
Margaret Buckingham Élue Membre le 29 novembre 2005 dans la section Biologie intégrative Directeur de recherche au CNRS, Professeur à l'Institut Pasteur Œuvre scientifique Margaret Buckingham, de nationalités française et britannique, née en 1945, est diplômée (B.A., M.A., D. Phil.) de l’université d’Oxford. Depuis 1971, elle a mené sa carrière scientifique en France, d’abord dans le laboratoire de François Gros, puis à partir de 1987, en tant que chef de l’Unité de génétique moléculaire du développement, puis Professeur à l’Institut Pasteur où elle a été directrice du Département de biologie du développement. Elle est directeur de recherche au CNRS. Elle a présidé la section de Biologie du développement et de la reproduction au CNRS de 2001 à 2004 et la Société Française de Biologie du Développement de 2008 à 2011. Elle est actuellement membre du Comité Consultatif National d’Ethique (CCNE). Les recherches de Margaret Buckingham portent sur les mécanismes qui conduisent une cellule naïve à entrer dans un programme de différenciation tissulaire pendant le développement de l’organisme. Elle étudie les gènes qui régulent la formation et la régénération du muscle de squelette, ainsi que les populations cellulaires qui forment le cœur. Margaret Buckingham a effectué des études pionnières sur l’organisation des gènes du muscle et leurs différents modes d’expression pendant le développement. Parmi les gènes des facteurs de régulation myogénique, de la famille MyoD, l’expression de Myf5 précède la myogenèse chez l’embryon. En son absence, les cellules adoptent d’autres destins cellulaires, démontrant ainsi le rôle de Myf5 comme facteur de détermination myogénique. -
Female Fellows of the Royal Society
Female Fellows of the Royal Society Professor Jan Anderson FRS [1996] Professor Ruth Lynden-Bell FRS [2006] Professor Judith Armitage FRS [2013] Dr Mary Lyon FRS [1973] Professor Frances Ashcroft FMedSci FRS [1999] Professor Georgina Mace CBE FRS [2002] Professor Gillian Bates FMedSci FRS [2007] Professor Trudy Mackay FRS [2006] Professor Jean Beggs CBE FRS [1998] Professor Enid MacRobbie FRS [1991] Dame Jocelyn Bell Burnell DBE FRS [2003] Dr Philippa Marrack FMedSci FRS [1997] Dame Valerie Beral DBE FMedSci FRS [2006] Professor Dusa McDuff FRS [1994] Dr Mariann Bienz FMedSci FRS [2003] Professor Angela McLean FRS [2009] Professor Elizabeth Blackburn AC FRS [1992] Professor Anne Mills FMedSci FRS [2013] Professor Andrea Brand FMedSci FRS [2010] Professor Brenda Milner CC FRS [1979] Professor Eleanor Burbidge FRS [1964] Dr Anne O'Garra FMedSci FRS [2008] Professor Eleanor Campbell FRS [2010] Dame Bridget Ogilvie AC DBE FMedSci FRS [2003] Professor Doreen Cantrell FMedSci FRS [2011] Baroness Onora O'Neill * CBE FBA FMedSci FRS [2007] Professor Lorna Casselton CBE FRS [1999] Dame Linda Partridge DBE FMedSci FRS [1996] Professor Deborah Charlesworth FRS [2005] Dr Barbara Pearse FRS [1988] Professor Jennifer Clack FRS [2009] Professor Fiona Powrie FRS [2011] Professor Nicola Clayton FRS [2010] Professor Susan Rees FRS [2002] Professor Suzanne Cory AC FRS [1992] Professor Daniela Rhodes FRS [2007] Dame Kay Davies DBE FMedSci FRS [2003] Professor Elizabeth Robertson FRS [2003] Professor Caroline Dean OBE FRS [2004] Dame Carol Robinson DBE FMedSci -
PAX3–FOXO1 Establishes Myogenic Super Enhancers and Confers BET Bromodomain
Published OnlineFirst April 26, 2017; DOI: 10.1158/2159-8290.CD-16-1297 RESEARCH ARTICLE PAX3–FOXO1 Establishes Myogenic Super Enhancers and Confers BET Bromodomain Vulnerability Berkley E. Gryder 1 , Marielle E. Yohe 1 , 2 , Hsien-Chao Chou 1 , Xiaohu Zhang 3 , Joana Marques 4 , Marco Wachtel4 , Beat Schaefer 4 , Nirmalya Sen 1 , Young Song 1 , Alberto Gualtieri 5 , Silvia Pomella 5 , Rossella Rota5 , Abigail Cleveland 1 , Xinyu Wen 1 , Sivasish Sindiri 1 , Jun S. Wei 1 , Frederic G. Barr 6 , Sudipto Das7 , Thorkell Andresson 7 , Rajarshi Guha 3 , Madhu Lal-Nag 3 , Marc Ferrer 3 , Jack F. Shern 1 , 2 , Keji Zhao8 , Craig J. Thomas 3 , and Javed Khan 1 Downloaded from cancerdiscovery.aacrjournals.org on September 29, 2021. © 2017 American Association for Cancer Research. 16-CD-16-1297_p884-899.indd 884 7/20/17 2:21 PM Published OnlineFirst April 26, 2017; DOI: 10.1158/2159-8290.CD-16-1297 ABSTRACT Alveolar rhabdomyosarcoma is a life-threatening myogenic cancer of children and ado- lescent young adults, driven primarily by the chimeric transcription factor PAX3–FOXO1. The mechanisms by which PAX3–FOXO1 dysregulates chromatin are unknown. We fi nd PAX3–FOXO1 repro- grams the cis -regulatory landscape by inducing de novo super enhancers. PAX3–FOXO1 uses super enhancers to set up autoregulatory loops in collaboration with the master transcription factors MYOG, MYOD, and MYCN. This myogenic super enhancer circuitry is consistent across cell lines and primary tumors. Cells harboring the fusion gene are selectively sensitive to small-molecule inhibition of protein targets induced by, or bound to, PAX3–FOXO1-occupied super enhancers. -
PAX3-FOXO1A Expression in Rhabdomyosarcoma Is Driven by the Targetable Nuclear Receptor NR4A1 Alexandra Lacey1, Aline Rodrigues-Hoffman2, and Stephen Safe1
Published OnlineFirst November 18, 2016; DOI: 10.1158/0008-5472.CAN-16-1546 Cancer Therapeutics, Targets, and Chemical Biology Research PAX3-FOXO1A Expression in Rhabdomyosarcoma Is Driven by the Targetable Nuclear Receptor NR4A1 Alexandra Lacey1, Aline Rodrigues-Hoffman2, and Stephen Safe1 Abstract Alveolar rhabdomyosarcoma (ARMS) is a devastating pediatric PAX3-FOXO1A. Mechanistic investigations revealed a requirement disease driven by expression of the oncogenic fusion gene PAX3- for the NR4A1/Sp4 complex to bind GC-rich promoter regions FOXO1A. In this study, we report overexpression of the nuclear to elevate transcription of the PAX3-FOXO1A gene. In parallel, receptor NR4A1 in rhabdomyosarcomas that is sufficient to NR4A1 also regulated expression of b1-integrin, which with PAX3- drive high expression of PAX3-FOXO1A there. RNAi-mediated FOXO1A, contributed to tumor cell migration that was blocked by silencing of NR4A1 decreased expression of PAX3-FOXO1A and C-DIM/NR4A1 antagonists. Taken together, our results provide a its downstream effector genes. Similarly, cell treatment with the preclinical rationale for the use of NR4A1 small-molecule antago- NR4A1 small-molecule antagonists 1,1-bis(3-indolyl)-1-(p- nists to treat ARMS and other rhabdomyosarcomas driven by hydroxy or p-carbomethoxyphenyl)methane (C-DIM) decreased PAX3-FOXO1A. Cancer Res; 77(3); 1–10. Ó2016 AACR. Introduction activity for NR4A1. In contrast, NR4A1 exhibits tumor promoter activity (6, 7) in solid tumors. NR4A1 is also overexpressed in Rhabdomyosarcoma is the most common soft-tissue sarco- tumors from patients with breast, lung, pancreatic, colon, and ma that is primarily observed in children and adolescents and ovarian cancer and is a negative prognostic factor for patients with accounts for 50% of all pediatric cancers and 50% of soft-tissue breast, lung, and ovarian cancer (9–15). -
PAX3-FOXO1A Expression in Rhabdomyosarcoma Is Driven by the Targetable Nuclear Receptor NR4A1 Alexandra Lacey1, Aline Rodrigues-Hoffman2, and Stephen Safe1
Published OnlineFirst November 18, 2016; DOI: 10.1158/0008-5472.CAN-16-1546 Cancer Therapeutics, Targets, and Chemical Biology Research PAX3-FOXO1A Expression in Rhabdomyosarcoma Is Driven by the Targetable Nuclear Receptor NR4A1 Alexandra Lacey1, Aline Rodrigues-Hoffman2, and Stephen Safe1 Abstract Alveolar rhabdomyosarcoma (ARMS) is a devastating pediatric PAX3-FOXO1A. Mechanistic investigations revealed a requirement disease driven by expression of the oncogenic fusion gene PAX3- for the NR4A1/Sp4 complex to bind GC-rich promoter regions FOXO1A. In this study, we report overexpression of the nuclear to elevate transcription of the PAX3-FOXO1A gene. In parallel, receptor NR4A1 in rhabdomyosarcomas that is sufficient to NR4A1 also regulated expression of b1-integrin, which with PAX3- drive high expression of PAX3-FOXO1A there. RNAi-mediated FOXO1A, contributed to tumor cell migration that was blocked by silencing of NR4A1 decreased expression of PAX3-FOXO1A and C-DIM/NR4A1 antagonists. Taken together, our results provide a its downstream effector genes. Similarly, cell treatment with the preclinical rationale for the use of NR4A1 small-molecule antago- NR4A1 small-molecule antagonists 1,1-bis(3-indolyl)-1-(p- nists to treat ARMS and other rhabdomyosarcomas driven by hydroxy or p-carbomethoxyphenyl)methane (C-DIM) decreased PAX3-FOXO1A. Cancer Res; 77(3); 1–10. Ó2016 AACR. Introduction activity for NR4A1. In contrast, NR4A1 exhibits tumor promoter activity (6, 7) in solid tumors. NR4A1 is also overexpressed in Rhabdomyosarcoma is the most common soft-tissue sarco- tumors from patients with breast, lung, pancreatic, colon, and ma that is primarily observed in children and adolescents and ovarian cancer and is a negative prognostic factor for patients with accounts for 50% of all pediatric cancers and 50% of soft-tissue breast, lung, and ovarian cancer (9–15). -
EMBO Conference Takes to the Sea Life Sciences in Portugal
SUMMER 2013 ISSUE 24 encounters page 3 page 7 Life sciences in Portugal The limits of privacy page 8 EMBO Conference takes to the sea EDITORIAL Maria Leptin, Director of EMBO, INTERVIEW EMBO Associate Member Tom SPOTLIGHT Read about how the EMBO discusses the San Francisco Declaration Cech shares his views on science in Europe and Courses & Workshops Programme funds on Research Assessment and some of the describes some recent productive collisions. meetings for life scientists in Europe. concerns about Journal Impact Factors. PAGE 2 PAGE 5 PAGE 9 www.embo.org COMMENTARY INSIDE SCIENTIFIC PUBLISHING panels have to evaluate more than a hundred The San Francisco Declaration on applicants to establish a short list for in-depth assessment, they cannot be expected to form their views by reading the original publications Research Assessment of all of the applicants. I believe that the quality of the journal in More than 7000 scientists and 250 science organizations have by now put which research is published can, in principle, their names to a joint statement called the San Francisco Declaration on be used for assessment because it reflects how the expert community who is most competent Research Assessment (DORA; am.ascb.org/dora). The declaration calls to judge it views the science. There has always on the world’s scientific community to avoid misusing the Journal Impact been a prestige factor associated with the publi- Factor in evaluating research for funding, hiring, promotion, or institutional cation of papers in certain journals even before the impact factor existed. This prestige is in many effectiveness. -
In Mediating Transcriptional Activity of Androgen Receptor Splice Variants
ROLE OF TRANSCRIPTIONAL ACTIVATION UNIT 5 (TAU5) IN MEDIATING TRANSCRIPTIONAL ACTIVITY OF ANDROGEN RECEPTOR SPLICE VARIANTS A THESIS SUBMITTED TO THE FACULTY OF THE GRADUATE SCHOOL OF THE UNIVERSITY OF MINNESOTA BY SARITA KUMARI MUTHA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE SCOTT DEHM & JIM McCARTHY DECEMBER 2012 © Sarita Kumari Mutha 2012 ACKNOWLEDGEMENTS I would like to thank the Dehm Lab: Scott Dehm, Yingming Li, Siu Chiu Chan, and Luke Brand for the support, discussions, journal clubs, and training. I would like to thank MCBD&G faculty Kathleen Conklin and Meg Titus for their support. Finally, I would also to acknowledge my committee Scott Dehm, Jim McCarthy, and Kaylee Schwertfeger for their time and support. i DEDICATION This thesis is dedicated to my mentor and advisor Scott Dehm. This work would not have been possible without his support. I am very grateful for my time under his mentorship and the opportunity to learn from him. ii ABSTRACT The standard treatment for advanced prostate cancer is chemical castration, which inhibits the activity of the androgen receptor (AR). Eventually, prostate cancer reemerges with a castration-resistant phenotype (CRPC) but still depends on AR signaling. One mechanism of AR activity in CRPC is the synthesis of AR splice variants, which lack the ligand binding domain. These splice variants function as constitutively active transcription factors that promote expression of endogenous AR target genes and support androgen independent prostate cancer cell growth. Previous work has shown transcriptional activation unit 5 (TAU5) is necessary for ligand independent activity of the full length AR in low or no androgen conditions and that this activation is mediated by the WHTLF motif. -
Margaret Buckingham, Discoveries in Skeletal and Cardiac Muscle Development, Elected to the National Academy of Science Michael a Rudnicki*
Rudnicki Skeletal Muscle 2012, 2:12 http://www.skeletalmusclejournal.com/content/2/1/12 Skeletal Muscle COMMENT Open Access Margaret Buckingham, discoveries in skeletal and cardiac muscle development, elected to the National Academy of Science Michael A Rudnicki* Abstract Margaret Buckingham was presented as a newly elected member to the National Academy of Sciences on 28 April 2012. Over the course of her career, Dr Buckingham made many seminal contributions to the understanding of skeletal muscle and cardiac development. Her studies on cardiac progenitor populations has provided insight into understanding heart malformations, while her work on skeletal muscle progenitors has elucidated their embryonic origins and the transcriptional hierarchies controlling their developmental progression. Keywords: National Academy of Sciences, Cardiac development, Skeletal muscle development Commentary Her work on cardiac progenitor populations is of clinical Dr Margaret Buckingham, a much-respected investigator importance in understanding heart malformations. who has made many significant contributions to our Dr Buckingham has also made major contributions to understanding of skeletal muscle and cardiac develop- the molecular genetic analysis of skeletal muscle devel- ment, was elected to the National Academy of Sciences in opment. She was the first to analyze expression of the 2011 and presented on 28 April, 2012. Dr Buckingham is myogenic regulatory factors of the MyoD family during Professor in the Department of Developmental Biology at mouse embryogenesis [9] and the behavior of cells in the the Pasteur Institute in Paris. She has been awarded many absence of Myf5 [10]. prestigious distinctions including that of Officier de la Lé- Her more recent work demonstrated that skeletal gion d’Honneur and Officier de l'Ordre National du Mér- muscle growth depends on a somite-derived population of ite, to name but two. -
PROGRAMME & Book of Abstracts
PROGRAMME & book of abstracts “. MOVING FORWARD TOGETHER” www.EDBC2019Alicante.com ORGANISED BY CONTENTS SPONSORS & COLLABORATORS ORGANIZATION .......................................................................... 4 GENERAL INFORMATION ......................................................... 5 INSTRUCTIONS FOR SPEAKERS AND AUTHORS ................ 8 CONGRESS TIMETABLE ............................................................ 9 SCIENTIFIC PROGRAMME WEDNESDAY 23 .................................................................... 12 THURSDAY 24 ........................................................................ 13 FRIDAY 25 ............................................................................... 16 SATURDAY 26 ........................................................................ 19 POSTER SESSIONS ................................................................... 21 EXHIBITORS AND SPONSORS ................................................ 48 ABSTRACTS ................................................................................ 51 AUTHORS’ INDEX ...................................................................... 263 4 EDBC2019 EDBC2019 5 ORGANIZATION GENERAL INFORMATION ORGANIZING COMMITTEE INVITED SPEAKERS VENUE Ángela Nieto. Alicante Enrique Amaya. Manchester Auditorio de la Diputación de Alicante - ADDA Víctor Borrell. Alicante Detlev Arendt. Heidelberg Paseo Campoamor, s/n Sergio Casas-Tintó. Madrid Laure Bally Cuif. Paris 03010 Alicante, Spain Pilar Cubas. Madrid Fernando Casares. Sevilla www.addaalicante.es -
Cardiac Cell Lineages That Form the Heart
This is a free sample of content from The Biology of Heart Disease. Click here for more information on how to buy the book. Cardiac Cell Lineages that Form the Heart Sigole` ne M. Meilhac1, Fabienne Lescroart2,Ce´ dric Blanpain2,3, and Margaret E. Buckingham1 1Institut Pasteur, Department of Developmental and Stem Cell Biology, CNRS URA2578, 75015 Paris, France 2Universite´ Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium 3WELBIO, Universite´ Libre de Bruxelles, Brussels B-1070, Belgium Correspondence: [email protected]; [email protected] Myocardial cells ensure the contractility of the heart, which also depends on other meso- dermal cell types for its function. Embryological experiments had identified the sources of cardiac precursorcells. With the advent of genetic engineering, novel tools have been used to reconstruct the lineage tree of cardiac cells that contribute to different parts of the heart, map the development of cardiac regions, and characterize their genetic signature. Such knowl- edge is of fundamental importance for our understanding of cardiogenesis and also for the diagnosis and treatment of heart malformations. he sources of cells that form the different tracing experiments based on the engineered Tparts of the heart and their relationships to temporal and spatial expression of a reporter each other are of major fundamental interest gene in different cardiac progenitors and their for understanding cardiogenesis. They are also descendants, with the mouse as the principal of biomedical significance in the context of model system. congenital heart malformations and for future therapeutic approaches to cardiac malfunction SOURCES OF CARDIAC CELLS IN THE based on stem cell therapies.