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Sebastián A García, Anka Swiersy, Praveen Radhakrishnan, Vittorio Branchi, Lahiri Kanth Nanduri, Balázs Győrffy, Alexander M Betzler, Ulrich Bork, Christoph Kahlert, Christoph Reißfelder, Nuh N Rahbari, Jürgen Weitz, Sebastian Schölch
BACKGROUND: Colorectal cancer (CRC) is the third most common cancer in western countries and is driven by the Wnt signaling pathway. LIM-domain-binding protein 1 (LDB1) interacts with the Wnt signaling pathway and has been connected to malignant diseases. We therefore aimed to evaluate the role of LDB1 in CRC. RESULTS: Overexpression of LDB1 in CRC is associated with strikingly reduced overall and metastasis free survival in all three independent patient cohorts...
October 5, 2016: Oncotarget
Keren Gueta, Ahuvit David, Tsadok Cohen, Yotam Menuchin-Lasowski, Hila Nobel, Ginat Narkis, LiQi Li, Paul Love, Jimmy de Melo, Seth Blackshaw, Heiner Westphal, Ruth Ashery-Padan
The Lim domain binding proteins (Ldbs) are key cofactor proteins that assemble with LIM domains of the LMO/LIM-HD family to form functional complexes that regulate cell proliferation and differentiation throughout the CNS. Here, using conditional mutagenesis and comparative phenotypic analysis, we analyze the function of Ldb1 and Ldb2 in mouse retinal development, and demonstrate overlapping and specific functions of both genes. We show that Ldb1 interacts with Lhx2 in the embryonic retina and that both Ldb1 and Ldb2, probably functioning with Lhx2 in a complex, play a key role in maintaining the pool of retinal progenitor cells...
October 3, 2016: Development
Laura Breda, Irene Motta, Silvia Lourenco, Chiara Gemmo, Wulan Deng, Jeremy W Rupon, Osheiza Y Abdulmalik, Deepa Manwani, Gerd A Blobel, Stefano Rivella
Overcoming the silencing of the fetal γ-globin gene has been a long-standing goal in the treatment of sickle cell disease (SCD). The major transcriptional enhancer of the β-globin locus, called the locus control region (LCR), dynamically interacts with the developmental stage-appropriate β-type globin genes via chromatin looping, a process requiring the protein Ldb1. In adult erythroid cells, the LCR can be redirected from the adult β- to the fetal γ-globin promoter by tethering Ldb1 to the human γ-globin promoter with custom-designed zinc finger (ZF) proteins (ZF-Ldb1), leading to reactivation of γ-globin gene expression...
August 25, 2016: Blood
Soojin Kim, Yangu Zhao, Ja-Myong Lee, Woon Ryoung Kim, Marat Gorivodsky, Heiner Westphal, Dongho Geum
LIM domain-binding protein 1 (Ldb1) is a nuclear cofactor that interacts with LIM homeodomain proteins to form multiprotein complexes that are important for transcription regulation. Ldb1 has been shown to play essential roles in various processes during mouse embryogenesis. To determine the role of Ldb1 in mid- and hindbrain development, we have generated a conditional mutant with a specific deletion of the Ldb1 in the Engrailed-1-expressing region of the developing mid- and hindbrain. Our study showed that the deletion impaired the expression of signaling molecules, such as fibroblast growth factor 8 (FGF8) and Wnt1, in the isthmic organizer and the expression of Shh in the ventral midbrain...
July 1, 2016: Stem Cells and Development
T Hoang, J A Lambert, R Martin
SCL, a transcription factor of the basic helix-loop-helix family, is a master regulator of hematopoiesis. Scl specifies lateral plate mesoderm to a hematopoietic fate and establishes boundaries by inhibiting the cardiac lineage. A combinatorial interaction between Scl and Vegfa/Flk1 sets in motion the first wave of primitive hematopoiesis. Subsequently, definitive hematopoietic stem cells (HSCs) emerge from the embryo proper via an endothelial-to-hematopoietic transition controlled by Runx1, acting with Scl and Gata2...
2016: Current Topics in Developmental Biology
K J Hewitt, K D Johnson, X Gao, S Keles, E H Bresnick
Transcriptional regulators mediate the genesis and function of the hematopoietic system by binding complex ensembles of cis-regulatory elements to establish genetic networks. While thousands to millions of any given cis-element resides in a genome, how transcriptional regulators select these sites and how site attributes dictate functional output is not well understood. An instructive system to address this problem involves the GATA family of transcription factors that control vital developmental and physiological processes and are linked to multiple human pathologies...
2016: Current Topics in Developmental Biology
Carolina A Braghini, Flavia C Costa, Halyna Fedosyuk, Renee Y Neades, Lesya V Novikova, Matthew P Parker, Robert D Winefield, Kenneth R Peterson
Fetal hemoglobin is a major genetic modifier of the phenotypic heterogeneity in patients with sickle cell disease and certain β-thalassemias. Normal levels of fetal hemoglobin postnatally are approximately 1% of total hemoglobin. Patients who have hereditary persistence of fetal hemoglobin, characterized by elevated synthesis of γ-globin in adulthood, show reduced disease pathophysiology. Hereditary persistence of fetal hemoglobin is caused by β-globin locus deletions (deletional hereditary persistence of fetal hemoglobin) or γ-globin gene promoter point mutations (non-deletional hereditary persistence of fetal hemoglobin)...
April 2016: Experimental Biology and Medicine
Carol Zygar Plautz, Hannah C Williams, Robert M Grainger
Identification of genes responsible for embryonic induction poses a number of challenges; to name a few, secreted molecules of interest may be low in abundance, may not be secreted but tethered to the signaling cell(s), or may require the presence of binding partners or upstream regulatory molecules. Thus in a search for gene products capable of eliciting an early lens-inductive response in competent ectoderm, we utilized an expression cloning system that would allow identification of paracrine or juxtacrine factors as well as transcriptional or other regulatory proteins...
2016: Journal of Visualized Experiments: JoVE
Dino P Leone, Georgia Panagiotakos, Whitney E Heavner, Pushkar Joshi, Yangu Zhao, Heiner Westphal, Susan K McConnell
Although many genes that specify neocortical projection neuron subtypes have been identified, the downstream effectors that control differentiation of those subtypes remain largely unknown. Here, we demonstrate that the LIM domain-binding proteins Ldb1 and Ldb2 exhibit dynamic and inversely correlated expression patterns during cerebral cortical development. Ldb1-deficient brains display severe defects in proliferation and changes in regionalization, phenotypes resembling those of Lhx mutants. Ldb2-deficient brains, on the other hand, exhibit striking phenotypes affecting layer 5 pyramidal neurons: Immature neurons have an impaired capacity to segregate into mature callosal and subcerebral projection neurons...
January 31, 2016: Cerebral Cortex
Justin H Layer, Catherine E Alford, W Hayes McDonald, Utpal P Davé
LMO2 is a component of multisubunit DNA-binding transcription factor complexes that regulate gene expression in hematopoietic stem and progenitor cell development. Enforced expression of LMO2 causes leukemia by inducing hematopoietic stem cell-like features in T-cell progenitor cells, but the biochemical mechanisms of LMO2 function have not been fully elucidated. In this study, we systematically dissected the LMO2/LDB1-binding interface to investigate the role of this interaction in T-cell leukemia. Alanine scanning mutagenesis of the LIM interaction domain of LDB1 revealed a discrete motif, R(320)LITR, required for LMO2 binding...
February 2016: Molecular and Cellular Biology
Ralph Stadhouders, Alba Cico, Tharshana Stephen, Supat Thongjuea, Petros Kolovos, H Irem Baymaz, Xiao Yu, Jeroen Demmers, Karel Bezstarosti, Alex Maas, Vilma Barroca, Christel Kockx, Zeliha Ozgur, Wilfred van Ijcken, Marie-Laure Arcangeli, Charlotte Andrieu-Soler, Boris Lenhard, Frank Grosveld, Eric Soler
How transcription factors (TFs) cooperate within large protein complexes to allow rapid modulation of gene expression during development is still largely unknown. Here we show that the key haematopoietic LIM-domain-binding protein-1 (LDB1) TF complex contains several activator and repressor components that together maintain an erythroid-specific gene expression programme primed for rapid activation until differentiation is induced. A combination of proteomics, functional genomics and in vivo studies presented here identifies known and novel co-repressors, most notably the ETO2 and IRF2BP2 proteins, involved in maintaining this primed state...
2015: Nature Communications
Ita Costello, Sonja Nowotschin, Xin Sun, Arne W Mould, Anna-Katerina Hadjantonakis, Elizabeth K Bikoff, Elizabeth J Robertson
Gene regulatory networks controlling functional activities of spatially and temporally distinct endodermal cell populations in the early mouse embryo remain ill defined. The T-box transcription factor Eomes, acting downstream from Nodal/Smad signals, directly activates the LIM domain homeobox transcription factor Lhx1 in the visceral endoderm. Here we demonstrate Smad4/Eomes-dependent Lhx1 expression in the epiblast marks the entire definitive endoderm lineage, the anterior mesendoderm, and midline progenitors...
October 15, 2015: Genes & Development
Luca Caputo, Hagen R Witzel, Petros Kolovos, Sirisha Cheedipudi, Mario Looso, Athina Mylona, Wilfred F J van IJcken, Karl-Ludwig Laugwitz, Sylvia M Evans, Thomas Braun, Eric Soler, Frank Grosveld, Gergana Dobreva
Cardiac stem/progenitor cells hold great potential for regenerative therapies; however, the mechanisms regulating their expansion and differentiation remain insufficiently defined. Here we show that Ldb1 is a central regulator of genome organization in cardiac progenitor cells, which is crucial for cardiac lineage differentiation and heart development. We demonstrate that Ldb1 binds to the key regulator of cardiac progenitors, Isl1, and protects it from degradation. Furthermore, the Isl1/Ldb1 complex promotes long-range enhancer-promoter interactions at the loci of the core cardiac transcription factors Mef2c and Hand2...
September 3, 2015: Cell Stem Cell
Lorna Wilkinson-White, Krystal L Lester, Nina Ripin, David A Jacques, J Mitchell Guss, Jacqueline M Matthews
The transcription factor GATA1 helps regulate the expression of thousands of genes involved in blood development, by binding to single or double GATA sites on DNA. An important part of gene activation is chromatin looping, the bringing together of DNA elements that lie up to many thousands of basepairs apart in the genome. It was recently suggested, based on studies of the closely related protein GATA3, that GATA-mediated looping may involve interactions of each of two zinc fingers (ZF) with distantly spaced DNA elements...
October 2015: Protein Science: a Publication of the Protein Society
Ivan Krivega, Colleen Byrnes, Jaira F de Vasconcellos, Y Terry Lee, Megha Kaushal, Ann Dean, Jeffery L Miller
Induction of fetal hemoglobin (HbF) production in adult erythrocytes can reduce the severity of sickle cell disease and β-thalassemia. Transcription of β-globin genes is regulated by the distant locus control region (LCR), which is brought into direct gene contact by the LDB1/GATA-1/TAL1/LMO2-containing complex. Inhibition of G9a H3K9 methyltransferase by the chemical compound UNC0638 activates fetal and represses adult β-globin gene expression in adult human hematopoietic precursor cells, but the underlying mechanisms are unclear...
July 30, 2015: Blood
Kyla D Baron, Khalid Al-Zahrani, Jillian Conway, Cédrik Labrèche, Christopher J Storbeck, Jane E Visvader, Luc A Sabourin
The Ste20-like kinase SLK plays a pivotal role in cell migration and focal adhesion turnover and is regulated by the LIM domain-binding proteins Ldb1 and Ldb2. These adapter proteins have been demonstrated to interact with LMO4 in the organization of transcriptional complexes. Therefore, we have assessed the ability of LMO4 to also interact and regulate SLK activity. Our data show that LMO4 can directly bind to SLK and activate its kinase activity in vitro and in vivo. LMO4 can be co-precipitated with SLK following the induction of cell migration by scratch wounding and Cre-mediated deletion of LMO4 in conditional LMO4(fl/fl) fibroblasts inhibits cell migration and SLK activation...
July 2015: Biochimica et Biophysica Acta
Feng Zhang, Bogdan Tanasa, Daria Merkurjev, Chijen Lin, Xiaoyuan Song, Wenbo Li, Yuliang Tan, Zhijie Liu, Jie Zhang, Kenneth A Ohgi, Anna Krones, Dorota Skowronska-Krawczyk, Michael G Rosenfeld
Substantial evidence supports the hypothesis that enhancers are critical regulators of cell-type determination, orchestrating both positive and negative transcriptional programs; however, the basic mechanisms by which enhancers orchestrate interactions with cognate promoters during activation and repression events remain incompletely understood. Here we report the required actions of LIM domain-binding protein 1 (LDB1)/cofactor of LIM homeodomain protein 2/nuclear LIM interactor, interacting with the enhancer-binding protein achaete-scute complex homolog 1, to mediate looping to target gene promoters and target gene regulation in corticotrope cells...
February 3, 2015: Proceedings of the National Academy of Sciences of the United States of America
Soumya Joseph, Ann H Kwan, Philippa H Stokes, Joel P Mackay, Liza Cubeddu, Jacqueline M Matthews
LIM-domain only protein 4 (LMO4) is a widely expressed protein with important roles in embryonic development and breast cancer. It has been reported to bind many partners, including the transcription factor Deformed epidermal autoregulatory factor-1 (DEAF1), with which LMO4 shares many biological parallels. We used yeast two-hybrid assays to show that DEAF1 binds both LIM domains of LMO4 and that DEAF1 binds the same face on LMO4 as two other LMO4-binding partners, namely LIM domain binding protein 1 (LDB1) and C-terminal binding protein interacting protein (CtIP/RBBP8)...
2014: PloS One
Carol Zygar Plautz, Brett E Zirkle, Malia J Deshotel, Robert M Grainger
BACKGROUND: Specific molecules involved in early inductive signaling from anterior neural tissue to the placodal ectoderm to establish a lens-forming bias, as well as their regulatory factors, remain largely unknown. In this study, we sought to identify and characterize these molecules. RESULTS: Using an expression cloning strategy to isolate genes with lens-inducing activity, we identified the transcriptional cofactor ldb1. This, together with evidence for its nuclear dependence, suggests its role as a regulatory factor, not a direct signaling molecule...
December 2014: Developmental Dynamics: An Official Publication of the American Association of Anatomists
June Li, Yasuhiro Kurasawa, Yang Wang, Karen Clise-Dwyer, Sherry A Klumpp, Hong Liang, Ramesh C Tailor, Aaron C Raymond, Zeev Estrov, Stephen J Brandt, Richard E Davis, Patrick Zweidler-McKay, Hesham M Amin, Lalitha Nagarajan
Transcriptional mechanisms governing hematopoietic stem cell (HSC) quiescence, self-renewal, and differentiation are not fully understood. Sequence-specific ssDNA-binding protein 2 (SSBP2) is a candidate acute myelogenous leukemia (AML) suppressor gene located at chromosome 5q14. SSBP2 binds the transcriptional adaptor protein Lim domain-binding protein 1 (LDB1) and enhances LDB1 stability to regulate gene expression. Notably, Ldb1 is essential for HSC specification during early development and maintenance in adults...
November 1, 2014: Journal of Immunology: Official Journal of the American Association of Immunologists
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