Open Access
Densely Interconnected Transcriptional Circuits Control Cell States in Human Hematopoiesis
Noa Novershtern,Noa Novershtern,Noa Novershtern,Aravind Subramanian,Lee N. Lawton,Raymond H. Mak,W. Nicholas Haining,Marie McConkey,Naomi Habib,Nir Yosef,Cindy Y. Chang,Cindy Y. Chang,Tal Shay,Garrett M. Frampton,Adam Drake,Ilya B. Leskov,Björn Nilsson,Björn Nilsson,Fred Preffer,David Dombkowski,John W. Evans,Ted Liefeld,John S. Smutko,Jianzhu Chen,Nir Friedman,Richard A. Young,Todd R. Golub,Todd R. Golub,Todd R. Golub,Aviv Regev,Aviv Regev,Aviv Regev,Benjamin L. Ebert,Benjamin L. Ebert,Benjamin L. Ebert +34 more
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TLDR
This work profiled gene expression in 38 distinct purified populations of human hematopoietic cells and used probabilistic models of gene expression and analysis of cis-elements in gene promoters to decipher the general organization of their regulatory circuitry.Abstract:
Though many individual transcription factors are known to regulate hematopoietic differentiation, major aspects of the global architecture of hematopoiesis remain unknown. Here, we profiled gene expression in 38 distinct purified populations of human hematopoietic cells and used probabilistic models of gene expression and analysis of cis-elements in gene promoters to decipher the general organization of their regulatory circuitry. We identified modules of highly coexpressed genes, some of which are restricted to a single lineage but most of which are expressed at variable levels across multiple lineages. We found densely interconnected cis-regulatory circuits and a large number of transcription factors that are differentially expressed across hematopoietic states. These findings suggest a more complex regulatory system for hematopoiesis than previously assumed.read more
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Revealing the vectors of cellular identity with single-cell genomics
TL;DR: Single-cell genomics has now made it possible to create a comprehensive atlas of human cells and has reopened definitions of a cell's identity and of the ways in which identity is regulated by the cell's molecular circuitry.
Seventy-five genetic loci influencing the human red blood cell
Pim van der Harst,Weihua Zhang,Irene Mateo Leach,Augusto Rendon,Niek Verweij,Joban Sehmi,Dirk S. Paul,Ulrich Elling,Hooman Allayee,Xinzhong Li,Aparna Radhakrishnan,Sian-Tsung Tan,Katrin Voss,Christian X. Weichenberger,Cornelis A. Albers,Abtehale Al-Hussani,Folkert W. Asselbergs,Marina Ciullo,Fabrice Danjou,Christian Dina,Tõnu Esko,David M. Evans,Lude Franke,Martin Goegele,Jaana Hartiala,Micha Hersch,Hilma Holm,Jouke-Jan Hottenga,Stavroula Kanoni,Marcus E. Kleber,Vasiliki Lagou,Claudia Langenberg,Lorna M. Lopez,Leo-Pekka Lyytikäinen,Olle Melander,Federico Murgia,Ilja M. Nolte,Paul F. O'Reilly,Sandosh Padmanabhan,Afshin Parsa,Nicola Pirastu,Eleonora Porcu,Laura Portas,Inga Prokopenko,Janina S. Ried,So-Youn Shin,Clara S. Tang,Alexander Teumer,Michela Traglia,Sheila Ulivi,Harm-Jan Westra,Jian Yang,Jing Hua Zhao,Franco Anni,Abdel Abdellaoui,Antony P. Attwood,Beverley Balkau,Stefania Bandinelli,François Bastardot,Beben Benyamin,Bernhard O. Boehm,William O.C.M. Cookson,Debashish Das,Paul I.W. de Bakker,Rudolf A. de Boer,Eco J. C. de Geus,Marleen H.M. de Moor,Maria Dimitriou,Francisco S. Domingues,Angela Doering,Gunnar Engström,Gudmundur I. Eyjolfsson,Luigi Ferrucci,Krista Fischer,Renzo Galanello,Stephen F. Garner,Bernd Genser,Quince Gibson,Giorgia Girotto,Daniel F. Gudbjartsson,Sarah E. Harris,Anna-Liisa Hartikainen,Claire E. Hastie,Bo Hedblad,Thomas Illig,Jennifer Jolley,Mika Kähönen,Ido P. Kema,John P. Kemp,Liming Liang,Heather Lloyd-Jones,Ruth J. F. Loos,Stuart Meacham,Sarah E. Medland,Christa Meisinger,Yasin Memari,Evelin Mihailov,Kathy Miller,Miriam F. Moffatt,Matthias Nauck,Maria Novatchkova,Teresa Nutile,Isleifur Olafsson,Pall T. Onundarson,Debora Parracciani,Brenda W.J.H. Penninx,Lucia Perseu,Antonio Piga,Giorgio Pistis,Anneli Pouta,Ursula Puc,Olli T. Raitakari,Susan M. Ring,Antonietta Robino,Daniela Ruggiero,Aimo Ruokonen,Aude Saint-Pierre,Cinzia Sala,Andres Salumets,Jennifer G. Sambrook,Hein Schepers,Carsten Oliver Schmidt,Herman H W Silljé,Robert Sladek,Johannes H. Smit,John M. Starr,Jonathan Stephens,Patrick Sulem,Toshiko Tanaka,Unnur Thorsteinsdottir,Vinicius Tragante,Wiek H. van Gilst,L. Joost van Pelt,Dirk J. van Veldhuisen,Uwe Voelker,John Whitfield,Gonneke Willemsen,Bernhard R. Winkelmann,Gerald Wirnsberger,Ale Algra,Francesco Cucca,Adamo Pio d'Adamo,John Danesh,Ian J. Deary,Anna F. Dominiczak,Paul Elliott,Paolo Fortina,Philippe Froguel,Paolo Gasparini,Andreas Greinacher,Stanley L. Hazen,Marjo-Riitta Järvelin,Kay-Tee Khaw,Terho Lehtimäki,Winfried Maerz,Nicholas G. Martin,Andres Metspalu,Braxton D. Mitchell,Grant W. Montgomery,Carmel Moore,Gerjan Navis,Mario Pirastu,Peter P. Pramstaller,Ramiro Ramirez-Solis,Eric E. Schadt,James Scott,Alan R. Shuldiner,George Davey Smith,J. Gustav Smith,Harold Snieder,Rossella Sorice,Tim D. Spector,Kari Stefansson,Michael Stumvoll,W.H. Wilson Tang,Daniela Toniolo,Anke Toenjes,Peter M. Visscher,Peter Vollenweider,Nicholas J. Wareham,Bruce H. R. Wolffenbuttel,Dorret I. Boomsma,Jacques S. Beckmann,George Dedoussis,Panos Deloukas,Manuel A. R. Ferreira,Serena Sanna,Manuela Uda,Andrew A. Hicks,Josef M. Penninger,Christian Gieger,Jaspal S. Kooner,Willem H. Ouwehand,Nicole Soranzo,John C. Chambers +194 more
TL;DR: In this article, the authors carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals and identified 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10−8, which together explain 4-9% of the phenotypic variance per trait.
HSF1 Drives a Transcriptional Program Distinct from Heat Shock to Support Highly Malignant Human Cancers
Marc L. Mendillo,Sandro Santagata,George W. Bell,Rong Hu,Rulla M. Tamimi,Ernest Fraenkel,Tan A. Ince,Luke Whitesell,Susan Lindquist,Martina Koeva +9 more
TL;DR: This work identifies an HSF1-regulated transcriptional program specific to highly malignant cells and distinct from heat shock, active in breast, colon and lung tumors isolated directly from human patients and strongly associated with metastasis and death.
The creatine kinase pathway is a metabolic vulnerability in EVI1-positive acute myeloid leukemia
Christopher F. Bassil,Issam Ben-Sahra,Lina Benajiba,Gabriela Alexe,Yana Pikman,Amy Saur Conway,Michael R. Burgess,Qing Li,Frederic Luciano,Patrick Auberger,Ilene Galinsky,Daniel J. DeAngelo,Richard Stone,Yi Zhang,Archibald S. Perkins,Kevin Shannon,Alexandre Puissant,Kimberly Stegmaier,Nina Fenouille,Azucena Ramos,Michael T. Hemann +20 more
TL;DR: In this paper, a screen using pooled short hairpin RNAs (shRNAs) identified the ATP-buffering, mitochondrial creatine kinase CKMT1 as necessary for survival of EVI1-expressing cells in subjects with acute myeloid leukemia (AML) and is associated with poor clinical outcome.
Dissertation
The Development of Chemical and Computational Tools to Study Transcriptional Regulation in Cancer
TL;DR: A subset of super enhancers are identified that promote off-target DNA damage from the B cell antibody diversity enzyme AID, leading to double strand break events and translocations in B cell malignancies.
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