ARID5B As a Critical Downstream Target of the TAL1 Complex That Activates the Oncogenic Transcriptional Program and Promotes T-Cell Leukemogenesis
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Novel TAL1 Targets Beyond Protein-Coding Genes: Identification of TAL1-Regulated Micrornas in T-Cell Acute Lymphoblastic Leukemia
Letters to the Editor 1603 REFERENCES 8 Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y, Yamamoto R et al. Frequent 1 Rozman C, Montserrat E. Chronic lymphocytic leukemia. N Engl J Med 1995; 333: pathway mutations of splicing machinery in myelodysplasia. Nature 2011; 478: 64–69. 1052–1057. 9 Papaemmanuil E, Cazzola M, Boultwood J, Malcovati L, Vyas P, Bowen D et al. 2 Zenz T, Mertens D, Kuppers R, Dohner H, Stilgenbauer S. From pathogenesis to Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. N Engl J Med treatment of chronic lymphocytic leukaemia. Nat Rev Cancer 2010; 10: 37–50. 2011; 365: 1384–1395. 3 Puente XS, Pinyol M, Quesada V, Conde L, Ordonez GR, Villamor N et al. Whole- 10 Damm F, Nguyen-Khac F, Fontenay M, Bernard OA. Spliceosome and other novel genome sequencing identifies recurrent mutations in chronic lymphocytic leu- mutations in chronic lymphocytic leukemia and myeloid malignancies. Leukemia kaemia. Nature 2011; 475: 101–105. 2012; 26: 2027–2031. 4 Quesada V, Conde L, Villamor N, Ordonez GR, Jares P, Bassaganyas L et al. Exome 11 Wahl MC, Will CL, Luhrmann R. The spliceosome: design principles of a dynamic sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in RNP machine. Cell 2009; 136: 701–718. chronic lymphocytic leukemia. Nat Genet 2012; 44: 47–52. 12 David CJ, Manley JL. Alternative pre-mRNA splicing regulation in cancer: pathways 5 Wang L, Lawrence MS, Wan Y, Stojanov P, Sougnez C, Stevenson K et al. SF3B1 and programs unhinged. Genes Dev 2010; 24: 2343–2364. -
Molecular and Physiological Basis for Hair Loss in Near Naked Hairless and Oak Ridge Rhino-Like Mouse Models: Tracking the Role of the Hairless Gene
University of Tennessee, Knoxville TRACE: Tennessee Research and Creative Exchange Doctoral Dissertations Graduate School 5-2006 Molecular and Physiological Basis for Hair Loss in Near Naked Hairless and Oak Ridge Rhino-like Mouse Models: Tracking the Role of the Hairless Gene Yutao Liu University of Tennessee - Knoxville Follow this and additional works at: https://trace.tennessee.edu/utk_graddiss Part of the Life Sciences Commons Recommended Citation Liu, Yutao, "Molecular and Physiological Basis for Hair Loss in Near Naked Hairless and Oak Ridge Rhino- like Mouse Models: Tracking the Role of the Hairless Gene. " PhD diss., University of Tennessee, 2006. https://trace.tennessee.edu/utk_graddiss/1824 This Dissertation is brought to you for free and open access by the Graduate School at TRACE: Tennessee Research and Creative Exchange. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of TRACE: Tennessee Research and Creative Exchange. For more information, please contact [email protected]. To the Graduate Council: I am submitting herewith a dissertation written by Yutao Liu entitled "Molecular and Physiological Basis for Hair Loss in Near Naked Hairless and Oak Ridge Rhino-like Mouse Models: Tracking the Role of the Hairless Gene." I have examined the final electronic copy of this dissertation for form and content and recommend that it be accepted in partial fulfillment of the requirements for the degree of Doctor of Philosophy, with a major in Life Sciences. Brynn H. Voy, Major Professor We have read this dissertation and recommend its acceptance: Naima Moustaid-Moussa, Yisong Wang, Rogert Hettich Accepted for the Council: Carolyn R. -
PHF2 Histone Demethylase Prevents DNA Damage and Genome Instability by Controlling Cell Cycle Progression of Neural Progenitors
PHF2 histone demethylase prevents DNA damage and genome instability by controlling cell cycle progression of neural progenitors Stella Pappaa, Natalia Padillab,c,1, Simona Iacobuccia,1, Marta Viciosoa, Elena Álvarez de la Campab,c, Claudia Navarroa, Elia Marcosa, Xavier de la Cruzb,c,2, and Marian A. Martínez-Balbása,2 aDepartment of Molecular Genomics, Instituto de Biología Molecular de Barcelona, Consejo Superior de Investigaciones Científicas, 08028 Barcelona, Spain; bClinical and Translational Bioinformatics, Vall d’Hebron Institute of Research, E-08035 Barcelona, Spain; and cInstitut Català per la Recerca i Estudis Avançats, 08018 Barcelona, Spain Edited by Robert E. Kingston, Massachusetts General Hospital/Harvard Medical School, Boston, MA, and approved August 6, 2019 (received for review February 25, 2019) Histone H3 lysine 9 methylation (H3K9me) is essential for cellular terestingly, PHF2 mutations have been found in patients with homeostasis; however, its contribution to development is not well autism spectrum disorder (ASD) (22–24). Despite PHF2 high established. Here, we demonstrate that the H3K9me2 demethy- expression in the neural tube and its implication on mental dis- lase PHF2 is essential for neural progenitor proliferation in vitro eases, PHF2 involvement in neural development has not yet and for early neurogenesis in the chicken spinal cord. Using genome- been explored. wide analyses and biochemical assays we show that PHF2 controls In this study, we analyzed the role of PHF2 in neural stem cell the expression of critical cell cycle progression genes, particularly (NSC) biology. We found that PHF2 is essential for progenitor those related to DNA replication, by keeping low levels of H3K9me3 proliferation in vitro and in vivo, in the chicken spinal cord. -
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. -
Transcritional Regulatory Networks Downstream of TAL1/SCL in T-Cell Acute Lymphoblastic Leukemia
Supplemental Materials Transcritional Regulatory Networks Downstream of TAL1/SCL in T-cell Acute Lymphoblastic Leukemia Palomero et al. Figure S1. Downregulation of TAL1 by RNA interference does not affect apoptosis in Jurkat cells. Figure S2. Scatter plots of Chromatin immunoprecipitations performed with TAL1#370 antibody in Jurkat cells. Figure S3. Target validation by gene-specific quantitative RT-PCR (qRT-PCR) Table S1. Genes regulated by TAL1 knockdown are identified as direct targets of this transcription factor using ChIP on chip. Table S2. Analysis of TAL1, E2A and HEB binding to TAL1 direct targets identified by ChIP on chip. Table S3. Previously described TAL1 targets. Figure S1. Downregulation of TAL1 by RNA interference does not affect apoptosis in Jurkat cells. Annexin V staining was used to quantify apoptosis rates in Jurkat cell clones expressing TAL1 shRNA (right panels) or a control shRNA (left panels). The percentage of apoptotic cells is indicated in the bottom right corner of each graph, while the dead cell percentage is indicated in the top right corner. PI: propidium iodide. Name Description p-value IFRD1 interferon-related developmental regulator 1 0.009927703 PCK2 phosphoenolpyruvate carboxykinase 2 (mitochondrial) 0.00445631 ATRX alpha thalassemia/mental retardation syndrome X-linked (RAD54 homolog, S. cerevisiae) 0.010847575 CDK6 cyclin-dependent kinase 6 0.044093956 Table S1. Genes regulated by TAL1 knockdown are identified as direct target of this transcription factor using ChIP on chip. The p-value determined by the error model applied to the ChIP on chip fluorescence data is indicated in the right column. Name Description Name Description E2A E2A HEB HEB TAL1 TAL1 Signal transduction-Receptor Transporters-lipids/small molecules MUC16 mucin 16 ABCC12 ATP-binding cassette, sub-fam. -
Function of Bromodomain and Extra-Terminal Motif Proteins (Bets) in Gata1-Mediated Transcription
University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2015 Function of Bromodomain and Extra-Terminal Motif Proteins (bets) in Gata1-Mediated Transcription Aaron James Stonestrom University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Molecular Biology Commons, and the Pharmacology Commons Recommended Citation Stonestrom, Aaron James, "Function of Bromodomain and Extra-Terminal Motif Proteins (bets) in Gata1-Mediated Transcription" (2015). Publicly Accessible Penn Dissertations. 1148. https://repository.upenn.edu/edissertations/1148 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/1148 For more information, please contact [email protected]. Function of Bromodomain and Extra-Terminal Motif Proteins (bets) in Gata1-Mediated Transcription Abstract Bromodomain and Extra-Terminal motif proteins (BETs) associate with acetylated histones and transcription factors. While pharmacologic inhibition of this ubiquitous protein family is an emerging therapeutic approach for neoplastic and inflammatory disease, the mechanisms through which BETs act remain largely uncharacterized. Here we explore the role of BETs in the physiologically relevant context of erythropoiesis driven by the transcription factor GATA1. First, we characterize functions of the BET family as a whole using a pharmacologic approach. We find that BETs are broadly required for GATA1-mediated transcriptional activation, but that repression is largely BET-independent. BETs support activation by facilitating both GATA1 occupancy and transcription downstream of its binding. Second, we test the specific olesr of BETs BRD2, BRD3, and BRD4 in GATA1-activated transcription. BRD2 and BRD4 are required for efficient anscriptionaltr activation by GATA1. Despite co-localizing with the great majority of GATA1 binding sites, we find that BRD3 is not equirr ed for GATA1-mediated transcriptional activation. -
Prox1regulates the Subtype-Specific Development of Caudal Ganglionic
The Journal of Neuroscience, September 16, 2015 • 35(37):12869–12889 • 12869 Development/Plasticity/Repair Prox1 Regulates the Subtype-Specific Development of Caudal Ganglionic Eminence-Derived GABAergic Cortical Interneurons X Goichi Miyoshi,1 Allison Young,1 Timothy Petros,1 Theofanis Karayannis,1 Melissa McKenzie Chang,1 Alfonso Lavado,2 Tomohiko Iwano,3 Miho Nakajima,4 Hiroki Taniguchi,5 Z. Josh Huang,5 XNathaniel Heintz,4 Guillermo Oliver,2 Fumio Matsuzaki,3 Robert P. Machold,1 and Gord Fishell1 1Department of Neuroscience and Physiology, NYU Neuroscience Institute, Smilow Research Center, New York University School of Medicine, New York, New York 10016, 2Department of Genetics & Tumor Cell Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, 3Laboratory for Cell Asymmetry, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan, 4Laboratory of Molecular Biology, Howard Hughes Medical Institute, GENSAT Project, The Rockefeller University, New York, New York 10065, and 5Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724 Neurogliaform (RELNϩ) and bipolar (VIPϩ) GABAergic interneurons of the mammalian cerebral cortex provide critical inhibition locally within the superficial layers. While these subtypes are known to originate from the embryonic caudal ganglionic eminence (CGE), the specific genetic programs that direct their positioning, maturation, and integration into the cortical network have not been eluci- dated. Here, we report that in mice expression of the transcription factor Prox1 is selectively maintained in postmitotic CGE-derived cortical interneuron precursors and that loss of Prox1 impairs the integration of these cells into superficial layers. Moreover, Prox1 differentially regulates the postnatal maturation of each specific subtype originating from the CGE (RELN, Calb2/VIP, and VIP). -
The Effect of Chromosomal Translocations in Acute Leukemias: the LMO2 Paradigm in Transcription and Development I
[CANCER RESEARCH (SUPPL.) 59, 1794s-1798s, April 1, 1999] The Effect of Chromosomal Translocations in Acute Leukemias: The LMO2 Paradigm in Transcription and Development I Terence H. Rabbitts, 2 Katharina Bucher, Grace Chung, Gerald Grutz, Alan Warren, and Yoshi Yamada Medical Research Council Laboratory of Molecular Biology, Division of Protein and Nucleic Acid Chemistry, Hills Road, Cambridge, CB2 2QH United Kingdom Abstract proto-oncogene from a Burkitt's lymphoma translocation breakpoint t(8;14)(q24;q32) revealed that, while the translocated gene was intact, Two general features have emerged about genes that are activated after there were many mutations in both the noncoding first exon and chromosomal translocations in acute forms of cancer. The protein prod- within the coding region itself (4-11). In T-cell acute leukemias, there ucts of these genes are transcription regulators and are involved in are several different chromosomal translocations found in individual developmental processes, and it seems that the subversion of these normal functions accounts for their role in tumorigenesis. The features of the tumors, and the analysis of these has led to the discovery of many LMO family of genes, which encode LIM-domain proteins involved in different, novel genes that can contribute to T-cell tumorigenesis (1). T-cell acute leukemia through chromosomal translocations, typify these These and many other studies have led to two conclusions: abnormal functions in tumorigenesis. For example, the LMO2 protein is (a) many of the chromosomal translocation-activated oncogenes are involved in the formation of multimeric DNA-binding complexes, which transcription regulators in their normal sites of expression, and it is may vary in composition at different stages of hematopoiesis and function this property that is instrumental in their involvement in tumor etiol- to control differentiation of specific lineages. -
Mutational Landscape Differences Between Young-Onset and Older-Onset Breast Cancer Patients Nicole E
Mealey et al. BMC Cancer (2020) 20:212 https://doi.org/10.1186/s12885-020-6684-z RESEARCH ARTICLE Open Access Mutational landscape differences between young-onset and older-onset breast cancer patients Nicole E. Mealey1 , Dylan E. O’Sullivan2 , Joy Pader3 , Yibing Ruan3 , Edwin Wang4 , May Lynn Quan1,5,6 and Darren R. Brenner1,3,5* Abstract Background: The incidence of breast cancer among young women (aged ≤40 years) has increased in North America and Europe. Fewer than 10% of cases among young women are attributable to inherited BRCA1 or BRCA2 mutations, suggesting an important role for somatic mutations. This study investigated genomic differences between young- and older-onset breast tumours. Methods: In this study we characterized the mutational landscape of 89 young-onset breast tumours (≤40 years) and examined differences with 949 older-onset tumours (> 40 years) using data from The Cancer Genome Atlas. We examined mutated genes, mutational load, and types of mutations. We used complementary R packages “deconstructSigs” and “SomaticSignatures” to extract mutational signatures. A recursively partitioned mixture model was used to identify whether combinations of mutational signatures were related to age of onset. Results: Older patients had a higher proportion of mutations in PIK3CA, CDH1, and MAP3K1 genes, while young- onset patients had a higher proportion of mutations in GATA3 and CTNNB1. Mutational load was lower for young- onset tumours, and a higher proportion of these mutations were C > A mutations, but a lower proportion were C > T mutations compared to older-onset tumours. The most common mutational signatures identified in both age groups were signatures 1 and 3 from the COSMIC database. -
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. -
Histone Demethylases at the Center of Cellular Differentiation and Disease
Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Erasing the methyl mark: histone demethylases at the center of cellular differentiation and disease Paul A.C. Cloos,2 Jesper Christensen, Karl Agger, and Kristian Helin1 Biotech Research and Innovation Centre (BRIC) and Centre for Epigenetics, University of Copenhagen, DK-2200 Copenhagen, Denmark The enzymes catalyzing lysine and arginine methylation impacts on the transcriptional activity of the underlying of histones are essential for maintaining transcriptional DNA by acting as a recognition template for effector programs and determining cell fate and identity. Until proteins modifying the chromatin environment and lead- recently, histone methylation was regarded irreversible. ing to either repression or activation. Thus, histone However, within the last few years, several families of methylation can be associated with either activation or histone demethylases erasing methyl marks associated repression of transcription depending on which effector with gene repression or activation have been identified, protein is being recruited. It should be noted that the underscoring the plasticity and dynamic nature of his- unmodified residues can also serve as a binding template tone methylation. Recent discoveries have revealed that for effector proteins leading to specific chromatin states histone demethylases take part in large multiprotein (Lan et al. 2007b). complexes synergizing with histone deacetylases, histone Arginine residues can be modified by one or two meth- methyltransferases, and nuclear receptors to control de- yl groups; the latter form in either a symmetric or asym- velopmental and transcriptional programs. Here we re- metric conformation (Rme1, Rme2s, and Rme2a), per- view the emerging biochemical and biological functions mitting a total of four states: one unmethylated and of the histone demethylases and discuss their potential three methylated forms. -
ARID5B Influences Anti-Metabolite Drug Sensitivity and Prognosis of Acute Lymphoblastic Leukemia
Author Manuscript Published OnlineFirst on October 1, 2019; DOI: 10.1158/1078-0432.CCR-19-0190 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. ARID5B influences antimetabolite drug sensitivity and prognosis of acute lymphoblastic leukemia Heng Xu1,2*, Xujie Zhao2*, Deepa Bhojwani3, Shuyu E2, Charnise Goodings2, Hui Zhang4,2, Nita L. Seibel5, Wentao Yang2, Chunliang Li6, William L. Carroll7, William Evans2,8, Jun J. Yang2,8 1Department of Laboratory Medicine, Precision Medicine Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China. 2Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA. 3Division of Hematology, Oncology, Blood and Marrow Transplantation, Children's Hospital Los Angeles, Los Angeles, California, USA. 4Department of Pediatric Hematology and Oncology, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong, China. 5Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland, USA. 6Department of Tumor Cell Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA. 7Departments of Pediatrics and Pathology, New York University Langone Medical Center, New York, New York, USA. 8Hematological Malignancies Program, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA Running title: ARID5B and drug resistance in ALL Keywords: acute lymphoblastic leukemia, ARID5B, p21, relapse, antimetabolite drug resistance *these authors contributed equally to this work. Financial support: This work was supported by the National Institutes of Health (GM118578, CA021765 and GM115279), the American Lebanese Syrian Associated Charities of St. Jude Children’s Research Hospital, and the Specialized Center of Research of Leukemia and Lymphoma Society (7010-14). Corresponding author: Jun J.