The Genome-Wide Dynamics of the Binding of Ldb1 Complexes During Erythroid Differentiation
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The Role of PU.1 and GATA-1 Transcription Factors During Normal and Leukemogenic Hematopoiesis
Leukemia (2010) 24, 1249–1257 & 2010 Macmillan Publishers Limited All rights reserved 0887-6924/10 www.nature.com/leu REVIEW The role of PU.1 and GATA-1 transcription factors during normal and leukemogenic hematopoiesis P Burda1, P Laslo2 and T Stopka1,3 1Department of Pathophysiology and Center of Experimental Hematology, First Faculty of Medicine, Charles University, Prague, Czech Republic; 2Section of Experimental Haematology, Leeds Institute of Molecular Medicine, University of Leads, St James’s University Hospital, Leeds, UK and 31st Department of Medicine-Hematology, General University Hospital, Prague, Czech Republic Hematopoiesis is coordinated by a complex regulatory network Additional domains include an N-terminal acidic domain and a of transcription factors and among them PU.1 (Spi1, Sfpi1) glutamine-rich domain, both involved in transcriptional activa- represents a key molecule. This review summarizes the tion, as well as a PEST domain involved in protein–protein indispensable requirement of PU.1 during hematopoietic cell fate decisions and how the function of PU.1 can be modulated interactions. PU.1 protein can be modified post-translationally by protein–protein interactions with additional factors. The by phosporylation at serines 41 (N-terminal acidic domain) and mutual negative regulation between PU.1 and GATA-1 is 142 and 148 (PEST domain), which results in augmented detailed within the context of normal and leukemogenic activity. hematopoiesis and the concept of ‘differentiation therapy’ to The PU.1 protein can physically interact with a variety of restore normal cellular differentiation of leukemic cells is regulatory factors including (i) general transcription factors discussed. Leukemia (2010) 24, 1249–1257; doi:10.1038/leu.2010.104; (TFIID, TBP), (ii) early hematopoietic transcription factors published online 3 June 2010 (GATA-2 and Runx-1), (iii) erythroid factor (GATA-1) and (iv) Keywords: PU.1; leukemia differentiation; GATA-1; chromatin; non-erythroid factors (C/EBPa, C/EBPb, IRF4/8 and c-Jun). -
Characterization of a Pediatric T-Cell Acute Lymphoblastic Leukemia Patient with Simultaneous LYL1 and LMO2 Rearrangements
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Erasmus University Digital Repository Articles and Brief Reports Acute Lymphoblastic Leukemia Characterization of a pediatric T-cell acute lymphoblastic leukemia patient with simultaneous LYL1 and LMO2 rearrangements Irene Homminga, 1 Maartje J. Vuerhard, 1 Anton W. Langerak, 2 Jessica Buijs-Gladdines, 1 Rob Pieters, 1 and Jules P.P. Meijerink 1 1Department of Pediatric Oncology/Hematology, Erasmus MC/Sophia Children’s Hospital, Rotterdam; and 2Department of Immunology, Erasmus MC, Rotterdam, The Netherlands ABSTRACT Translocation of the LYL1 oncogene are rare in T-cell acute consistently clustered along with cases having TAL1 or lymphoblastic leukemia, whereas the homologous TAL1 LMO2 rearrangements. Therefore, LYL1 -rearranged cases are gene is rearranged in approximately 20% of patients. not necessarily associated with immature T-cell develop - Previous gene-expression studies have identified an imma - ment, despite high LYL1 levels, but elicit a TALLMO expres - ture T-cell acute lymphoblastic leukemia subgroup with high sion signature. LYL1 expression in the absence of chromosomal aberrations. Molecular characterization of a t(7;19)(q34;p13) in a pediatric Key words: T-ALL, pediatric, LYL1, LMO2, rearrangements. T-cell acute lymphoblastic leukemia patient led to the identi - fication of a translocation between the TRB@ and LYL1 loci. Citation: Homminga I, Vuerhard MJ, Langerak AW, Buijs- Similar to incidental T-cell acute lymphoblastic leukemia Gladdines J, Pieters R, and Meijerink JPP. Characterization of a cases with synergistic, double translocations affecting pediatric T-cell acute lymphoblastic leukemia patient with simul - TAL1/2 and LMO1/2 oncogenes, this LYL1 -translocated taneous LYL1 and LMO2 rearrangements. -
DNA·RNA Triple Helix Formation Can Function As a Cis-Acting Regulatory
DNA·RNA triple helix formation can function as a cis-acting regulatory mechanism at the human β-globin locus Zhuo Zhoua, Keith E. Gilesa,b,c, and Gary Felsenfelda,1 aLaboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892; bUniversity of Alabama at Birmingham Stem Cell Institute, University of Alabama at Birmingham, Birmingham, AL 35294; and cDepartment of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294 Contributed by Gary Felsenfeld, February 4, 2019 (sent for review January 4, 2019; reviewed by James Douglas Engel and Sergei M. Mirkin) We have identified regulatory mechanisms in which an RNA tran- of the criteria necessary to establish the presence of a triplex script forms a DNA duplex·RNA triple helix with a gene or one of its structure, we first describe and characterize triplex formation at regulatory elements, suggesting potential auto-regulatory mecha- the FAU gene in human erythroid K562 cells. FAU encodes a nisms in vivo. We describe an interaction at the human β-globin protein that is a fusion containing fubi, a ubiquitin-like protein, locus, in which an RNA segment embedded in the second intron of and ribosomal protein S30. Although fubi function is unknown, the β-globin gene forms a DNA·RNA triplex with the HS2 sequence posttranslational processing produces S30, a component of the within the β-globin locus control region, a major regulator of glo- 40S ribosome. We used this system to refine methods necessary bin expression. We show in human K562 cells that the triplex is to detect triplex formation and to distinguish it from R-loop stable in vivo. -
Bioinformatic Analysis of Structure and Function of LIM Domains of Human Zyxin Family Proteins
International Journal of Molecular Sciences Article Bioinformatic Analysis of Structure and Function of LIM Domains of Human Zyxin Family Proteins M. Quadir Siddiqui 1,† , Maulik D. Badmalia 1,† and Trushar R. Patel 1,2,3,* 1 Alberta RNA Research and Training Institute, Department of Chemistry and Biochemistry, University of Lethbridge, 4401 University Drive, Lethbridge, AB T1K 3M4, Canada; [email protected] (M.Q.S.); [email protected] (M.D.B.) 2 Department of Microbiology, Immunology and Infectious Disease, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive, Calgary, AB T2N 4N1, Canada 3 Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB T6G 2E1, Canada * Correspondence: [email protected] † These authors contributed equally to the work. Abstract: Members of the human Zyxin family are LIM domain-containing proteins that perform critical cellular functions and are indispensable for cellular integrity. Despite their importance, not much is known about their structure, functions, interactions and dynamics. To provide insights into these, we used a set of in-silico tools and databases and analyzed their amino acid sequence, phylogeny, post-translational modifications, structure-dynamics, molecular interactions, and func- tions. Our analysis revealed that zyxin members are ohnologs. Presence of a conserved nuclear export signal composed of LxxLxL/LxxxLxL consensus sequence, as well as a possible nuclear localization signal, suggesting that Zyxin family members may have nuclear and cytoplasmic roles. The molecular modeling and structural analysis indicated that Zyxin family LIM domains share Citation: Siddiqui, M.Q.; Badmalia, similarities with transcriptional regulators and have positively charged electrostatic patches, which M.D.; Patel, T.R. -
Ldb1 Is Essential for Development of Nkx2.1 Lineage Derived Gabaergic and Cholinergic Neurons in the Telencephalon
Developmental Biology 385 (2014) 94–106 Contents lists available at ScienceDirect Developmental Biology journal homepage: www.elsevier.com/locate/developmentalbiology Ldb1 is essential for development of Nkx2.1 lineage derived GABAergic and cholinergic neurons in the telencephalon Yangu Zhao a,n,1, Pierre Flandin b,2, Daniel Vogt b, Alexander Blood a, Edit Hermesz a,3, Heiner Westphal a, John L. R. Rubenstein b,nn a Program on Genomics of Differentiation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA b Department of Psychiatry and the Nina Ireland Laboratory of Developmental Neurobiology, University of California San Francisco, San Francisco, CA 94143, USA article info abstract Article history: The progenitor zones of the embryonic mouse ventral telencephalon give rise to GABAergic and cholinergic Received 1 June 2013 neurons. We have shown previously that two LIM-homeodomain (LIM-HD) transcription factors, Lhx6 and Received in revised form Lhx8, that are downstream of Nkx2.1, are critical for the development of telencephalic GABAergic and 8 October 2013 cholinergic neurons. Here we investigate the role of Ldb1, a nuclear protein that binds directly to all LIM-HD Accepted 9 October 2013 factors, in the development of these ventral telencephalon derived neurons. We show that Ldb1 is expressed Available online 21 October 2013 in the Nkx2.1 cell lineage during embryonic development and in mature neurons. Conditional deletion of Ldb1 Keywords: causes defects in the expression of a series of genes in the ventral telencephalon and severe impairment in the Differentiation tangential migration of cortical interneurons from the ventral telencephalon. -
Open Dogan Phdthesis Final.Pdf
The Pennsylvania State University The Graduate School Eberly College of Science ELUCIDATING BIOLOGICAL FUNCTION OF GENOMIC DNA WITH ROBUST SIGNALS OF BIOCHEMICAL ACTIVITY: INTEGRATIVE GENOME-WIDE STUDIES OF ENHANCERS A Dissertation in Biochemistry, Microbiology and Molecular Biology by Nergiz Dogan © 2014 Nergiz Dogan Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy August 2014 ii The dissertation of Nergiz Dogan was reviewed and approved* by the following: Ross C. Hardison T. Ming Chu Professor of Biochemistry and Molecular Biology Dissertation Advisor Chair of Committee David S. Gilmour Professor of Molecular and Cell Biology Anton Nekrutenko Professor of Biochemistry and Molecular Biology Robert F. Paulson Professor of Veterinary and Biomedical Sciences Philip Reno Assistant Professor of Antropology Scott B. Selleck Professor and Head of the Department of Biochemistry and Molecular Biology *Signatures are on file in the Graduate School iii ABSTRACT Genome-wide measurements of epigenetic features such as histone modifications, occupancy by transcription factors and coactivators provide the opportunity to understand more globally how genes are regulated. While much effort is being put into integrating the marks from various combinations of features, the contribution of each feature to accuracy of enhancer prediction is not known. We began with predictions of 4,915 candidate erythroid enhancers based on genomic occupancy by TAL1, a key hematopoietic transcription factor that is strongly associated with gene induction in erythroid cells. Seventy of these DNA segments occupied by TAL1 (TAL1 OSs) were tested by transient transfections of cultured hematopoietic cells, and 56% of these were active as enhancers. Sixty-six TAL1 OSs were evaluated in transgenic mouse embryos, and 65% of these were active enhancers in various tissues. -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
5045.Full.Pdf
IFN Consensus Sequence Binding Protein (Icsbp) Is Critical for Eosinophil Development This information is current as Maja Milanovic, Grzegorz Terszowski, Daniela Struck, of September 28, 2021. Oliver Liesenfeld and Dirk Carstanjen J Immunol 2008; 181:5045-5053; ; doi: 10.4049/jimmunol.181.7.5045 http://www.jimmunol.org/content/181/7/5045 Downloaded from References This article cites 47 articles, 33 of which you can access for free at: http://www.jimmunol.org/content/181/7/5045.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 28, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology IFN Consensus Sequence Binding Protein (Icsbp) Is Critical for Eosinophil Development1 Maja Milanovic,2* Grzegorz Terszowski,2† Daniela Struck,2‡ Oliver Liesenfeld,‡ and Dirk Carstanjen3* IFN consensus sequence binding protein (Icsbp) (IFN response factor-8) is a hematopoietic transcription factor with dual functions in myelopoiesis and immunity. -
Transcriptome Analysis of Gravitational Effects on Mouse Skeletal Muscles Under Microgravity and Artificial 1 G Onboard Environm
www.nature.com/scientificreports OPEN Transcriptome analysis of gravitational efects on mouse skeletal muscles under microgravity and artifcial 1 g onboard environment Risa Okada1,2, Shin‑ichiro Fujita3,4, Riku Suzuki5,6, Takuto Hayashi3,5, Hirona Tsubouchi5, Chihiro Kato5,7, Shunya Sadaki5, Maho Kanai5,6, Sayaka Fuseya3,5, Yuri Inoue3,5, Hyojung Jeon5, Michito Hamada5, Akihiro Kuno5,6, Akiko Ishii8, Akira Tamaoka8, Jun Tanihata9, Naoki Ito10, Dai Shiba1,2, Masaki Shirakawa1,2, Masafumi Muratani1,4, Takashi Kudo1,5* & Satoru Takahashi1,5* Spacefight causes a decrease in skeletal muscle mass and strength. We set two murine experimental groups in orbit for 35 days aboard the International Space Station, under artifcial earth‑gravity (artifcial 1 g; AG) and microgravity (μg; MG), to investigate whether artifcial 1 g exposure prevents muscle atrophy at the molecular level. Our main fndings indicated that AG onboard environment prevented changes under microgravity in soleus muscle not only in muscle mass and fber type composition but also in the alteration of gene expression profles. In particular, transcriptome analysis suggested that AG condition could prevent the alterations of some atrophy‑related genes. We further screened novel candidate genes to reveal the muscle atrophy mechanism from these gene expression profles. We suggest the potential role of Cacng1 in the atrophy of myotubes using in vitro and in vivo gene transductions. This critical project may accelerate the elucidation of muscle atrophy mechanisms. Gravity is the most constant factor afecting the entire process of evolution of organisms on Earth. As adapting to a changing environment is key for any organism’s survival, the constant mechanical stimulus of gravitational force has been shared by all organisms on Earth through evolution 1. -
4-6 Weeks Old Female C57BL/6 Mice Obtained from Jackson Labs Were Used for Cell Isolation
Methods Mice: 4-6 weeks old female C57BL/6 mice obtained from Jackson labs were used for cell isolation. Female Foxp3-IRES-GFP reporter mice (1), backcrossed to B6/C57 background for 10 generations, were used for the isolation of naïve CD4 and naïve CD8 cells for the RNAseq experiments. The mice were housed in pathogen-free animal facility in the La Jolla Institute for Allergy and Immunology and were used according to protocols approved by the Institutional Animal Care and use Committee. Preparation of cells: Subsets of thymocytes were isolated by cell sorting as previously described (2), after cell surface staining using CD4 (GK1.5), CD8 (53-6.7), CD3ε (145- 2C11), CD24 (M1/69) (all from Biolegend). DP cells: CD4+CD8 int/hi; CD4 SP cells: CD4CD3 hi, CD24 int/lo; CD8 SP cells: CD8 int/hi CD4 CD3 hi, CD24 int/lo (Fig S2). Peripheral subsets were isolated after pooling spleen and lymph nodes. T cells were enriched by negative isolation using Dynabeads (Dynabeads untouched mouse T cells, 11413D, Invitrogen). After surface staining for CD4 (GK1.5), CD8 (53-6.7), CD62L (MEL-14), CD25 (PC61) and CD44 (IM7), naïve CD4+CD62L hiCD25-CD44lo and naïve CD8+CD62L hiCD25-CD44lo were obtained by sorting (BD FACS Aria). Additionally, for the RNAseq experiments, CD4 and CD8 naïve cells were isolated by sorting T cells from the Foxp3- IRES-GFP mice: CD4+CD62LhiCD25–CD44lo GFP(FOXP3)– and CD8+CD62LhiCD25– CD44lo GFP(FOXP3)– (antibodies were from Biolegend). In some cases, naïve CD4 cells were cultured in vitro under Th1 or Th2 polarizing conditions (3, 4). -
The Role of Noncoding Mutations in Blood Cancers Sunniyat Rahman and Marc R
© 2019. Published by The Company of Biologists Ltd | Disease Models & Mechanisms (2019) 12, dmm041988. doi:10.1242/dmm.041988 REVIEW The role of noncoding mutations in blood cancers Sunniyat Rahman and Marc R. Mansour* ABSTRACT survival in adult acute myeloid leukaemia (AML) and ALL are The search for oncogenic mutations in haematological malignancies still less than 50%, with significant treatment challenges including has largely focused on coding sequence variants. These variants treatment-resistant disease, clonal heterogeneity of the underlying have been critical in understanding these complex cancers in greater disease, treatment-associated toxicities and poor tolerance for detail, ultimately leading to better disease monitoring, subtyping and intensive treatment regimens, particularly in older patients with prognostication. In contrast, the search for oncogenic variants in the comorbidities (Kansagra et al., 2018). Because of this, there is a noncoding genome has proven to be challenging given the vastness significant impetus to discover new genetic aberrations, including of the search space, the intrinsic difficulty in assessing the impact of driver mutations (see Box 1 for a glossary of terms), that may variants that do not code for functional proteins, and our still primitive provide insight into the mechanisms of malignant haematopoiesis, understanding of the function harboured by large parts of the as well as offering novel therapeutic opportunities. noncoding genome. Recent studies have broken ground on this Detailed genetic characterisation of haematological malignancies quest, identifying somatically acquired and recurrent mutations in the has already identified alterations that are now being used for better noncoding genome that activate the expression of proto-oncogenes. diagnosis, prognostication, subtype identification and to inform In this Review, we explore some of the best-characterised examples therapeutic decisions (Taylor et al., 2017). -
LMO T-Cell Translocation Oncogenes Typify Genes Activated by Chromosomal Translocations That Alter Transcription and Developmental Processes
Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press PERSPECTIVE LMO T-cell translocation oncogenes typify genes activated by chromosomal translocations that alter transcription and developmental processes Terence H. Rabbitts1 Medical Research Council (MRC) Laboratory of Molecular Biology, Division of Protein and Nucleic Acid Chemistry, Cambridge CB2 2QH, UK The cytogenetic analysis of tumors, particularly those of ment (immunoglobulin or T-cell receptor) occurs and oc- hematopoietic origin, has revealed that reciprocal chro- casionally mediates chromosomal translocation. This mosomal translocations are recurring features of these type of translocation causes oncogene activation result- tumors. Further from the initial recognition of the trans- ing from the new chromosomal environment of the re- location t(9;22) (Nowell and Hungerford 1960; Rowley arranged gene. In general, this means inappropriate gene 1973), it has become clear that particular chromosomal expression. The second, and probably the most common translocations are found consistently in specific tumor outcome of chromosomal translocations, is gene fusion subtypes. A principle example of this is the translocation in which exons from a gene on each of the involved chro- t(8;14)(q24;q32.1) invariably found in the human B cell mosomes are linked after the chromosomal transloca- tumor Burkitt’s lymphoma (Manolov and Manolov 1972; tion, resulting in a fusion mRNA and protein. This type Zech et al. 1976). The link with the immunoglobulin of event is found in many cases of hematopoietic tumors H-chain locus on chromosome 14, band q32.1 (Croce et and in the sarcomas. al. 1979; Hobart et al.