Onto TFIID Function TATA Box That Can Impose Cell Specificity
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Microglia Emerge from Erythromyeloid Precursors Via Pu.1- and Irf8-Dependent Pathways
ART ic LE S Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways Katrin Kierdorf1,2, Daniel Erny1, Tobias Goldmann1, Victor Sander1, Christian Schulz3,4, Elisa Gomez Perdiguero3,4, Peter Wieghofer1,2, Annette Heinrich5, Pia Riemke6, Christoph Hölscher7,8, Dominik N Müller9, Bruno Luckow10, Thomas Brocker11, Katharina Debowski12, Günter Fritz1, Ghislain Opdenakker13, Andreas Diefenbach14, Knut Biber5,15, Mathias Heikenwalder16, Frederic Geissmann3,4, Frank Rosenbauer6 & Marco Prinz1,17 Microglia are crucial for immune responses in the brain. Although their origin from the yolk sac has been recognized for some time, their precise precursors and the transcription program that is used are not known. We found that mouse microglia were derived from primitive c-kit+ erythromyeloid precursors that were detected in the yolk sac as early as 8 d post conception. + lo − + − + These precursors developed into CD45 c-kit CX3CR1 immature (A1) cells and matured into CD45 c-kit CX3CR1 (A2) cells, as evidenced by the downregulation of CD31 and concomitant upregulation of F4/80 and macrophage colony stimulating factor receptor (MCSF-R). Proliferating A2 cells became microglia and invaded the developing brain using specific matrix metalloproteinases. Notably, microgliogenesis was not only dependent on the transcription factor Pu.1 (also known as Sfpi), but also required Irf8, which was vital for the development of the A2 population, whereas Myb, Id2, Batf3 and Klf4 were not required. Our data provide cellular and molecular insights into the origin and development of microglia. Microglia are the tissue macrophages of the brain and scavenge dying have the ability to give rise to microglia and macrophages in vitro cells, pathogens and molecules using pattern recognition receptors and in vivo under defined conditions. -
The Transcription Factors C-Myb and GATA-2 Act Independently in The
Proc. Natl. Acad. Sci. USA Vol. 93, pp. 5313-5318, May 1996 Medical Sciences The transcription factors c-myb and GATA-2 act independently in the regulation of normal hematopoiesis PAOLA MELOTrl AND BRUNO CALABRETTA Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107 Communicated by Sidney Weinhouse, Thomas Jefferson University, Philadelphia, PA, January 23, 1996 (received for review, October 20, 1995) ABSTRACT The transcription factors c-myb and GATA-2 erythromyeloid differentiation (7). This process appears to are both required for blood cell development in vivo and in rest in the ability of c-myb to activate the expression of vitro. However, very little is known on their mechanism(s) of hematopoiesis-specific targets such as c-kit,flt-3, GATA-1, and action and whether they impact on complementary or over- CD34, but not GATA-2 (7). The induction of c-kit and flt-3 lapping pathways of hematopoietic proliferation and differ- expression and the dependence of c-myb-transfected ES cells entiation. We report here that embryonic stem (ES) cells on the expression of these cytokine receptors for their prolif- transfected with c-myb or GATA-2 cDNAs, individually or in eration (7) strongly suggest that the up-regulation of growth combination, underwent hematopoietic commitment and dif- factor receptor levels is of fundamental importance for the ferentiation in the absence of added hematopoietic growth expansion of progenitor cells. In turn, such a process is factors but that stimulation with c-kit and flt-3 ligands en- probably a requirement for completion of the differentiation hanced colony formation only in the c-myb transfectants. -
Cells Transformed by a V-Myb-Estrogen Receptor Fusion Differentiate Into Multinucleated Giant Cells
JOURNAL OF VIROLOGY, May 1997, p. 3760–3766 Vol. 71, No. 5 0022-538X/97/$04.0010 Copyright q 1997, American Society for Microbiology Cells Transformed by a v-Myb-Estrogen Receptor Fusion Differentiate into Multinucleated Giant Cells UTE ENGELKE, DUEN-MEI WANG, AND JOSEPH S. LIPSICK* Department of Pathology, Stanford University School of Medicine, Stanford, California 94305-5324 Received 22 October 1996/Accepted 29 January 1997 In order to make conditional alleles of the v-myb oncogene, we constructed and tested avian retroviruses which produce a number of different fusion proteins between v-Myb and the human estrogen receptor (ER). We found that the portion of the ER used in making these fusions profoundly affected their transcriptional activation. However, all the fusions tested were only weakly transforming in embryonic yolk sac assays and there was no direct correlation between the level of transcriptional activation and strength of oncogenic transformation. Nevertheless, transformation by a v-Myb-ER fusion was estrogen dependent, and upon with- drawal of the hormone, monocytic-lineage cells differentiated into multinucleated giant cells. Surprisingly, the withdrawal of estrogen caused a dramatic increase in the stability of the fusion protein, although it remained unable to promote cell growth or block differentiation. Conditional alleles of retroviral oncogenes have provided genes, have been isolated and analyzed in considerable detail powerful tools with which to dissect the mechanism of onco- (3, 4). A differential cDNA screen has identified a target gene, genic transformation and the biology of transformed cells (17, mim-1, which is directly activated by the Gag-Myb-Ets protein 29). -
A Flexible Microfluidic System for Single-Cell Transcriptome Profiling
www.nature.com/scientificreports OPEN A fexible microfuidic system for single‑cell transcriptome profling elucidates phased transcriptional regulators of cell cycle Karen Davey1,7, Daniel Wong2,7, Filip Konopacki2, Eugene Kwa1, Tony Ly3, Heike Fiegler2 & Christopher R. Sibley 1,4,5,6* Single cell transcriptome profling has emerged as a breakthrough technology for the high‑resolution understanding of complex cellular systems. Here we report a fexible, cost‑efective and user‑ friendly droplet‑based microfuidics system, called the Nadia Instrument, that can allow 3′ mRNA capture of ~ 50,000 single cells or individual nuclei in a single run. The precise pressure‑based system demonstrates highly reproducible droplet size, low doublet rates and high mRNA capture efciencies that compare favorably in the feld. Moreover, when combined with the Nadia Innovate, the system can be transformed into an adaptable setup that enables use of diferent bufers and barcoded bead confgurations to facilitate diverse applications. Finally, by 3′ mRNA profling asynchronous human and mouse cells at diferent phases of the cell cycle, we demonstrate the system’s ability to readily distinguish distinct cell populations and infer underlying transcriptional regulatory networks. Notably this provided supportive evidence for multiple transcription factors that had little or no known link to the cell cycle (e.g. DRAP1, ZKSCAN1 and CEBPZ). In summary, the Nadia platform represents a promising and fexible technology for future transcriptomic studies, and other related applications, at cell resolution. Single cell transcriptome profling has recently emerged as a breakthrough technology for understanding how cellular heterogeneity contributes to complex biological systems. Indeed, cultured cells, microorganisms, biopsies, blood and other tissues can be rapidly profled for quantifcation of gene expression at cell resolution. -
Preinitiation Complex
Science Highlight – June 2011 Transcription Starts Here: Structural Models of a “Minimal” Preinitiation Complex RNA polymerase II (pol II) plays a central role in the regulation of gene expression. Pol II is the enzyme responsible for synthesizing all the messenger RNA (mRNA) and most of the small nuclear RNA (snRNA) in eukaryotes. One of the key questions for transcription is how pol II decides where to start on the genomic DNA to specifically and precisely turn on a gene. This is achieved during transcription initiation by concerted actions of the core enzyme pol II and a myriad of transcription factors including five general transcription factors, known as TFIIB, -D, -E, -F, -H, which together form a giant transcription preinitiation complex on a promoter prior to transcription. One of the most prominent core promoter DNA elements is the TATA box, usually directing transcription of tissue-specific genes. TATA-box binding protein (TBP), a key component of TFIID, recognizes the TATA DNA sequence. Based on the previous crystallographic studies, the TATA box DNA is bent by nearly 90 degree through the binding of TBP (1). This striking structural feature is thought to serve as a physical landmark for the location of active genes on the genome. In addition, the location of the TATA box at least in part determines the transcription start site (TSS) in most eukaryotes, including humans. The distance between the TATA box and the TSS is conserved at around 30 base pairs. TBP does not contact pol II directly and the TATA-containing promoter must be directed to the core enzyme through another essential transcription factor TFIIB. -
Molecular Biology and Applied Genetics
MOLECULAR BIOLOGY AND APPLIED GENETICS FOR Medical Laboratory Technology Students Upgraded Lecture Note Series Mohammed Awole Adem Jimma University MOLECULAR BIOLOGY AND APPLIED GENETICS For Medical Laboratory Technician Students Lecture Note Series Mohammed Awole Adem Upgraded - 2006 In collaboration with The Carter Center (EPHTI) and The Federal Democratic Republic of Ethiopia Ministry of Education and Ministry of Health Jimma University PREFACE The problem faced today in the learning and teaching of Applied Genetics and Molecular Biology for laboratory technologists in universities, colleges andhealth institutions primarily from the unavailability of textbooks that focus on the needs of Ethiopian students. This lecture note has been prepared with the primary aim of alleviating the problems encountered in the teaching of Medical Applied Genetics and Molecular Biology course and in minimizing discrepancies prevailing among the different teaching and training health institutions. It can also be used in teaching any introductory course on medical Applied Genetics and Molecular Biology and as a reference material. This lecture note is specifically designed for medical laboratory technologists, and includes only those areas of molecular cell biology and Applied Genetics relevant to degree-level understanding of modern laboratory technology. Since genetics is prerequisite course to molecular biology, the lecture note starts with Genetics i followed by Molecular Biology. It provides students with molecular background to enable them to understand and critically analyze recent advances in laboratory sciences. Finally, it contains a glossary, which summarizes important terminologies used in the text. Each chapter begins by specific learning objectives and at the end of each chapter review questions are also included. -
Transcription Regulation of MYB: a Potential and Novel Therapeutic Target in Cancer
Review Article Page 1 of 11 Transcription regulation of MYB: a potential and novel therapeutic target in cancer Partha Mitra1,2 1Pre-clinical Division, Vaxxas Pty. Ltd. Translational Research Institute, Woolloongabba QLD 4102, Australia; 2Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Woolloongabba QLD 4102, Australia Correspondence to: Partha Mitra. Pre-clinical Division, Vaxxas Pty. Ltd. Translational Research Institute, 37 Kent St., Woolloongabba QLD 4102, Australia; Queensland University of Technology, Translational Research Institute, 37 Kent St., Woolloongabba QLD 4102, Australia. Email: [email protected]; [email protected]. Abstract: Basal transcription factors have never been considered as a priority target in the field of drug discovery. However, their unparalleled roles in decoding the genetic information in response to the appropriate signal and their association with the disease progression are very well-established phenomena. Instead of considering transcription factors as such a target, in this review, we discuss about the potential of the regulatory mechanisms that control their gene expression. Based on our recent understanding about the critical roles of c-MYB at the cellular and molecular level in several types of cancers, we discuss here how MLL-fusion protein centred SEC in leukaemia, ligand-estrogen receptor (ER) complex in breast cancer (BC) and NF-κB and associated factors in colorectal cancer regulate the transcription of this gene. We further discuss plausible strategies, specific to each cancer type, to target those bona fide activators/co-activators, which control the regulation of this gene and therefore to shed fresh light in targeting the transcriptional regulation as a novel approach to the future drug discovery in cancer. -
Tnlo-Encoded Tet Repressor Can Regulate an Operator-Containing
Proc. Nati. Acad. Sci. USA Vol. 85, pp. 1394-1397, March 1988 Biochemistry TnlO-encoded tet repressor can regulate an operator-containing plant promoter (cauliflower mosaic virus 35S promoter/electroporation/transient chloramphenicol acetyltransferase assays) CHRISTIANE GATZ* AND PETER H. QUAILt Departments of Botany and Genetics, University of Wisconsin, Madison, WI 53706 Communicated by Folke Skoog, October 26, 1987 (receivedfor review July S, 1987) ABSTRACT The TnlO-encoded tet repressor-operator The TnlO-encoded tet repressor regulates the expression system was used to regulate transcription from the cauliflower of the Tc resistance operon by binding to nearly identical mosaic virus (CaMV) 35S promoter. Expression was moni- operator sequences that overlap with three divergent pro- tored in a transient assay system by using electric field- moters (14, 15). The genes of the tet operon are only mediated gene transfer ("electroporation") into tobacco pro- transcribed in the presence of the inducer Tc, which pre- toplasts. The tet repressor, being expressed in the plant cells vents the repressor from binding to its operator sequences. under the control of eukaryotic transcription signals, blocks The tet repressor was chosen for regulating a plant promoter transcription of a CaMV 35S promoter chloramphenicol ace- for two reasons. (i) With a native molecular mass of 48 kDa, tyltransferase (cat) fusion gene when the two tet operators diffusion into the nucleus seemed likely (16). (ii) The high flank the "TATA" box. In the presence of the inducer equilibrium association constant of the repressor-inducer tetracycline, expression is restored to full activity. Location of complex ensures efficient induction at sublethal Tc concen- the operators 21 base pairs downstream of the transcription trations (17), thus making the system useful as an on/off start site does not significantly affect transcription in the switch for the specific regulation of transferred genes. -
Transcriptional Plasticity Drives Leukemia Immune Escape
bioRxiv preprint doi: https://doi.org/10.1101/2021.08.23.457351; this version posted August 24, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Transcriptional plasticity drives leukemia immune escape Kenneth Eagle1,2*, Taku Harada1,*, Jérémie Kalfon3, Monika W. Perez1, Yaser Heshmati1, Jazmin Ewers1, Jošt Vrabič Koren4, Joshua M. Dempster3, Guillaume Kugener3, Vikram R. Paralkar5, Charles Y. Lin4 , Neekesh V. Dharia1,3, Kimberly Stegmaier1,3, Stuart H. Orkin1,6,† and Maxim Pimkin1,3,† 1. Cancer and Blood Disorders Center, Dana-Farber Cancer Institute and Boston Children’s Hospital, Harvard Medical School, Boston, MA 2. Ken Eagle Consulting, Houston, TX 3. Broad Institute of MIT and Harvard, Cambridge, MA 4. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 5. Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 6. Howard Hughes Medical Institute, Boston, MA * These authors contributed equally † These authors jointly supervised Correspondence to: [email protected], [email protected] ABSTRACT Relapse of acute myeloid leukemia (AML) after allogeneic bone marrow transplantation (alloSCT) has been linked to immune evasion due to reduced expression of major histocompatibility complex class II (MHC-II) proteins through unknown mechanisms. We developed CORENODE, a computational algorithm for genome-wide transcription network decomposition, that identified the transcription factors (TFs) IRF8 and MEF2C as positive regulators and MYB and MEIS1 as negative regulators of MHC-II expression in AML cells. -
MYB Transcription Factors and Its Regulation in Secondary Cell Wall Formation and Lignin Biosynthesis During Xylem Development
International Journal of Molecular Sciences Review MYB Transcription Factors and Its Regulation in Secondary Cell Wall Formation and Lignin Biosynthesis during Xylem Development Ruixue Xiao 1,2, Chong Zhang 2, Xiaorui Guo 2, Hui Li 1,2 and Hai Lu 1,2,* 1 Beijing Advanced Innovation Center for Tree Breeding by Molecular Design, Beijing Forestry University, Beijing 100083, China; [email protected] (R.X.); [email protected] (H.L.) 2 College of Biological Sciences and Biotechnology, Beijing Forestry University, Beijing 100083, China; [email protected] (C.Z.); [email protected] (X.G.) * Correspondence: [email protected] Abstract: The secondary wall is the main part of wood and is composed of cellulose, xylan, lignin, and small amounts of structural proteins and enzymes. Lignin molecules can interact directly or indirectly with cellulose, xylan and other polysaccharide molecules in the cell wall, increasing the mechanical strength and hydrophobicity of plant cells and tissues and facilitating the long-distance transportation of water in plants. MYBs (v-myb avian myeloblastosis viral oncogene homolog) belong to one of the largest superfamilies of transcription factors, the members of which regulate secondary cell-wall formation by promoting/inhibiting the biosynthesis of lignin, cellulose, and xylan. Among them, MYB46 and MYB83, which comprise the second layer of the main switch of secondary cell-wall biosynthesis, coordinate upstream and downstream secondary wall synthesis-related transcription factors. In addition, MYB transcription factors other than MYB46/83, as well as noncoding RNAs, Citation: Xiao, R.; Zhang, C.; Guo, X.; hormones, and other factors, interact with one another to regulate the biosynthesis of the secondary Li, H.; Lu, H. -
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Thynn HN, Chen XF, Dong SS, Guo Y, Yang TL. Commentary: An Allele-Specific Functional SNP Associated with Two Systemic Autoimmune Diseases Modulates IRF5 Expression by Long-Range Chromatin Loop Formation. J Immunological Sci. (2020); 4(1): 6-9 Journal of Immunological Sciences Commentary Article Open Access Commentary: An Allele-Specific Functional SNP Associated with Two Systemic Autoimmune Diseases Modulates IRF5 Expression by Long- Range Chromatin Loop Formation Hlaing Nwe Thynn, Xiao-Feng Chen, Shan-Shan Dong, Yan Guo, Tie-Lin Yang* Key Laboratory of Biomedical Information Engineering of Ministry of Education, Biomedical Informatics & Genomics Center, School of Life Science and Technol- ogy, Xi’an Jiaotong University, Xi’an, Shaanxi 710049, P. R. China Systemic Lupus Erythematosus (SLE) and Systemic Sclerosis Article Info Article Notes sharing similar pathogenic features. Genetic factors play important Received: February 14, 2020 (SSc) are two typical inflammatory systemic1 autoimmune diseases Accepted: March 20, 2020 roles in the pathogenesis of both diseases . We have witnessed huge success of genome-wide association studies (GWASs) in identifying *Correspondence: hundreds of susceptibility genetic variants associated with SLE Dr. Tie-Lin Yang, Ph.D., Key Laboratory of Biomedical Information Engineering of Ministry of Education, Biomedical and SSc, however, over 90% of which are located in noncoding Informatics & Genomics Center, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, Shaanxi into biological insights towards clinical applications. Currently, 710049, P. R. China; Telephone No: 86-29-82668463; Email: regions. It is challenging and important to translate GWAS findings [email protected]. compared with traditional genetic association studies, functional studies characterizing causal functional variants and downstream © 2020 Yang TL. -
Pan-HDAC Inhibitors Restore PRDM1 Response to IL21 in CREBBP
Published OnlineFirst October 22, 2018; DOI: 10.1158/1078-0432.CCR-18-1153 Cancer Therapy: Preclinical Clinical Cancer Research Pan-HDAC Inhibitors Restore PRDM1 Response to IL21 in CREBBP-Mutated Follicular Lymphoma Fabienne Desmots1,2, Mikael€ Roussel1,2,Celine Pangault1,2, Francisco Llamas-Gutierrez3,Cedric Pastoret1,2, Eric Guiheneuf2,Jer ome^ Le Priol2, Valerie Camara-Clayette4, Gersende Caron1,2, Catherine Henry5, Marc-Antoine Belaud-Rotureau5, Pascal Godmer6, Thierry Lamy1,7, Fabrice Jardin8, Karin Tarte1,9, Vincent Ribrag4, and Thierry Fest1,2 Abstract Purpose: Follicular lymphoma arises from a germinal cen- is enriched in the potent inducer of PRDM1 and IL21, highly ter B-cell proliferation supported by a bidirectional crosstalk produced by Tfhs. In follicular lymphoma carrying CREBBP with tumor microenvironment, in particular with follicular loss-of-function mutations, we found a lack of IL21-mediated helper T cells (Tfh). We explored the relation that exists PRDM1 response associated with an abnormal increased between the differentiation arrest of follicular lymphoma cells enrichment of the BCL6 protein repressor in PRDM1 gene. and loss-of-function of CREBBP acetyltransferase. Moreover, in these follicular lymphoma cells, pan-HDAC Experimental Design: The study used human primary cells inhibitor, vorinostat, restored their PRDM1 response to IL21 obtained from either follicular lymphoma tumors character- by lowering BCL6 bound to PRDM1. This finding was rein- ized for somatic mutations, or inflamed tonsils for normal forced by our exploration of patients with follicular lympho- germinal center B cells. Transcriptome and functional analyses ma treated with another pan-HDAC inhibitor. Patients were done to decipher the B- and T-cell crosstalk.