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https://www.readbyqxmd.com/read/28299656/roles-of-the-runx1-enhancer-in-normal-hematopoiesis-and-leukemogenesis
#1
Wei-Siang Liau, Phuong Cao Thi Ngoc, Takaomi Sanda
Enhancers are regulatory elements in genomic DNA that contain specific sequence motifs that are bound by DNA-binding transcription factors. The activity of enhancers is tightly regulated in an integrated and combinatorial manner, thus yielding complex patterns of transcription in different tissues. Identifying enhancers is crucial to understanding the physiological and pathogenic roles of their target genes. The RUNX1 intronic enhancer, eR1, acts in cis to regulate RUNX1 gene expression in hematopoietic stem cells (HSCs) and hemogenic endothelial cells...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28296634/constitutive-scaffolding-of-multiple-wnt-enhanceosome-components-by-legless-bcl9
#2
Laurens M van Tienen, Juliusz Mieszczanek, Marc Fiedler, Trevor J Rutherford, Mariann Bienz
Wnt/β-catenin signaling elicits context-dependent transcription switches that determine normal development and oncogenesis. These are mediated by the Wnt enhanceosome, a multiprotein complex binding to the Pygo chromatin reader and acting through TCF/LEF-responsive enhancers. Pygo renders this complex Wnt-responsive, by capturing β-catenin via the Legless/BCL9 adaptor. We used CRISPR/Cas9 genome engineering of Drosophila legless (lgs) and human BCL9 and B9L to show that the C-terminus downstream of their adaptor elements is crucial for Wnt responses...
March 15, 2017: ELife
https://www.readbyqxmd.com/read/28296185/chip-ldb1-interacts-with-tailup-islet1-to-regulate-cardiac-gene-expression-in-drosophila
#3
Kathrin Werner, Cornelia Donow, Petra Pandur
The LIM-homeodomain transcription factor Tailup (Tup) is a component of the complex cardiac transcriptional network governing specification and differentiation of cardiac cells in Drosophila. LIM-domain containing factors are known to interact with the adaptor molecule Chip/Ldb1 to form higher order protein complexes to regulate gene expression thereby determining a cell's developmental fate. However, with respect to Drosophila heart development, it has not been investigated yet, whether Chip and tup interact to regulate the generation of different cardiac cell types...
March 15, 2017: Genesis: the Journal of Genetics and Development
https://www.readbyqxmd.com/read/28179281/scl-tal1-a-multi-faceted-regulator-from-blood-development-to-disease
#4
Catherine Porcher, Hedia Chagraoui, Maiken S Kristiansen
SCL/TAL1 is an essential transcription factor in normal and malignant hematopoiesis. It is required for specification of the blood program during development, adult hematopoietic stem cell (HSC) survival and quiescence, and terminal maturation of select blood lineages. Following ectopic expression, SCL contributes to oncogenesis in T-cell acute lymphoblastic leukemia (T-ALL). Remarkably, SCL's activities are all mediated through nucleation of a core quaternary protein complex (SCL:E-protein:LMO2:LDB1) and dynamic recruitment of conserved combinatorial associations of additional regulators in a lineage- and stage-specific context...
February 8, 2017: Blood
https://www.readbyqxmd.com/read/28123038/intron-1-gata-site-enhances-alas2-expression-indispensably-during-erythroid-differentiation
#5
Yingchi Zhang, Jingliao Zhang, Wenbin An, Yang Wan, Shihui Ma, Jie Yin, Xichuan Li, Jie Gao, Weiping Yuan, Ye Guo, James Douglas Engel, Lihong Shi, Tao Cheng, Xiaofan Zhu
The first intronic mutations in the intron 1 GATA site (int-1-GATA) of 5-aminolevulinate synthase 2 (ALAS2) have been identified in X-linked sideroblastic anemia (XLSA) pedigrees, strongly suggesting it could be causal mutations of XLSA. However, the function of this int-1-GATA site during in vivo development remains largely unknown. Here, we generated mice lacking a 13 bp fragment, including this int-1-GATA site (T AGATAA: AGCCCC) and found that hemizygous deletion led to an embryonic lethal phenotype due to severe anemia resulting from a lack of ALAS2 expression, indicating that this non-coding sequence is indispensable for ALAS2 expression in vivo Further analyses revealed that this int-1-GATA site anchored the GATA site in intron 8 (int-8-GATA) and the proximal promoter, forming a long-range loop to enhance ALAS2 expression by an enhancer complex including GATA1, TAL1, LMO2, LDB1 and Pol II at least, in erythroid cells...
January 25, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28009534/ldb1-regulates-energy-homeostasis-during-diet-induced-obesity
#6
Christine Loyd, Yanping Liu, Teayoun Kim, Cassie Holleman, Jamie Galloway, Maigen Bethea, Benjamin N Ediger, Yawen Tang, Thomas A Swain, Doris A Stoffers, Glenn C Rowe, Martin Young, Chad Steele, Kirk M Habegger, Chad S Hunter
The broadly-expressed transcriptional coregulator, Ldb1, is essential for β-cell development and glucose homeostasis. However, it is unclear whether Ldb1 has metabolic roles beyond the β-cell, especially under metabolic stress. Global Ldb1 deletion results in early embryonic lethality; thus, we utilized global heterozygous Ldb1(+/-) and inducible β-cell-specific Ldb1-deficient (Ldb1(Δβ-cell)) mice. We assessed glucose and insulin tolerance, body composition, feeding, and energy expenditure during high-fat diet exposure...
December 23, 2016: Endocrinology
https://www.readbyqxmd.com/read/27941246/lim-domain-binding-1-maintains-the-terminally-differentiated-state-of-pancreatic-%C3%AE-cells
#7
Benjamin N Ediger, Hee-Woong Lim, Christine Juliana, David N Groff, LaQueena T Williams, Giselle Dominguez, Jin-Hua Liu, Brandon L Taylor, Erik R Walp, Vasumathi Kameswaran, Juxiang Yang, Chengyang Liu, Chad S Hunter, Klaus H Kaestner, Ali Naji, Changhong Li, Maike Sander, Roland Stein, Lori Sussel, Kyoung-Jae Won, Catherine Lee May, Doris A Stoffers
The recognition of β cell dedifferentiation in type 2 diabetes raises the translational relevance of mechanisms that direct and maintain β cell identity. LIM domain-binding protein 1 (LDB1) nucleates multimeric transcriptional complexes and establishes promoter-enhancer looping, thereby directing fate assignment and maturation of progenitor populations. Many terminally differentiated endocrine cell types, however, remain enriched for LDB1, but its role is unknown. Here, we have demonstrated a requirement for LDB1 in maintaining the terminally differentiated status of pancreatic β cells...
January 3, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27941244/%C3%AE-cells-led-astray-by-transcription-factors-and-the-company-they-keep
#8
Peter Thompson, Anil Bhushan
Pancreatic β cells have one of the highest protein secretion burdens in the body, as these cells must synthesize and secrete insulin in proportion to postprandial rises in blood glucose. Remarkably, it is now becoming clear that adult β cells retain plasticity and can dedifferentiate into embryonic fates or adopt alternate islet endocrine cell identities. This property is especially important, because changes in cell fate alter β cell function and could form the basis for defects in insulin secretion that occur early in the pathogenesis of the most prevalent form of β cell dysfunction, type 2 diabetes...
January 3, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27780223/lim-only-protein-4-lmo4-and-lim-domain-binding-protein-1-ldb1-promote-growth-and-metastasis-of-human-head-and-neck-cancer-lmo4-and-ldb1-in-head-and-neck-cancer
#9
Elizabeth A Simonik, Ying Cai, Katherine N Kimmelshue, Dana M Brantley-Sieders, Holli A Loomans, Claudia D Andl, Grant M Westlake, Victoria M Youngblood, Jin Chen, Wendell G Yarbrough, Brandee T Brown, Lalitha Nagarajan, Stephen J Brandt
Squamous cell carcinoma of the head and neck (HNSCC) accounts for more than 300,000 deaths worldwide per year as a consequence of tumor cell invasion of adjacent structures or metastasis. LIM-only protein 4 (LMO4) and LIM-domain binding protein 1 (LDB1), two directly interacting transcriptional adaptors that have important roles in normal epithelial cell differentiation, have been associated with increased metastasis, decreased differentiation, and shortened survival in carcinoma of the breast. Here, we implicate two LDB1-binding proteins, single-stranded binding protein 2 (SSBP2) and 3 (SSBP3), in controlling LMO4 and LDB1 protein abundance in HNSCC and in regulating specific tumor cell functions in this disease...
2016: PloS One
https://www.readbyqxmd.com/read/27713177/ldb1-overexpression-is-a-negative-prognostic-factor-in-colorectal-cancer
#10
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
https://www.readbyqxmd.com/read/27697904/the-stage-dependent-roles-of-ldb1-and-functional-redundancy-with-ldb2-in-mammalian-retinogenesis
#11
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 are key co-factor proteins that assemble with LIM domains of the LMO/LIM-HD family to form functional complexes that regulate cell proliferation and differentiation. 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 proteins. Ldb1 interacts with Lhx2 in the embryonic retina and both Ldb1 and Ldb2 play a key role in maintaining the pool of retinal progenitor cells...
November 15, 2016: Development
https://www.readbyqxmd.com/read/27405777/forced-chromatin-looping-raises-fetal-hemoglobin-in-adult-sickle-cells-to-higher-levels-than-pharmacologic-inducers
#12
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
https://www.readbyqxmd.com/read/27171818/ldb1-is-essential-for-the-development-of-isthmic-organizer-and-midbrain-dopaminergic-neurons
#13
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
https://www.readbyqxmd.com/read/27137657/scl-tal1-in-hematopoiesis-and-cellular-reprogramming
#14
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
https://www.readbyqxmd.com/read/27137654/the-hematopoietic-stem-and-progenitor-cell-cistrome-gata-factor-dependent-cis-regulatory-mechanisms
#15
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
https://www.readbyqxmd.com/read/26946532/original-research-generation-of-non-deletional-hereditary-persistence-of-fetal-hemoglobin-%C3%AE-globin-locus-yeast-artificial-chromosome-transgenic-mouse-models-175-black-hpfh-and-195-brazilian-hpfh
#16
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
https://www.readbyqxmd.com/read/26862700/functional-cloning-using-a-xenopus-oocyte-expression-system
#17
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...
January 30, 2016: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/26830346/compensatory-actions-of-ldb-adaptor-proteins-during-corticospinal-motor-neuron-differentiation
#18
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
https://www.readbyqxmd.com/read/26598604/lmo2-oncoprotein-stability-in-t-cell-leukemia-requires-direct-ldb1-binding
#19
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...
November 23, 2015: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/26593974/control-of-developmentally-primed-erythroid-genes-by-combinatorial-co-repressor-actions
#20
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...
November 23, 2015: Nature Communications
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