DOCSLIB.ORG

Shah Et Al 2019 Bioessays ACCEPTED VERSION

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Shah Et Al 2019 Bioessays ACCEPTED VERSION Hit and run transcriptional repressors are difficult to catch in the act Manan Shah1, Alister P.W. Funnell1,2, Kate G.R. Quinlan1 and Merlin Crossley1 1School of Biotechnology and Biomolecular Sciences, UNSW Sydney, Sydney, New South Wales, Australia 2Altius Institute for Biomedical Sciences, Seattle, Washington, USA *Corresponding Author: [email protected] Abstract Transcriptional silencing may not necessarily depend on continuous residence of a sequence- specific repressor at a control element and may act via a ‘hit and run’ mechanism. Due to limitations in assays that detect transcription factor (TF) binding, such as ChIP-Seq, this phenomenon may be challenging to detect and therefore its prevalence may be underappreciated. To explore this possibility we analysed erythroid gene promoters that are repressed directly by GATA1 in an inducible system. We found many repressed genes after bound immediately after induction of GATA1 but the residency of GATA1 decreases over time particularly at repressed genes. Furthermore, we show that the repressive mark H3K27me3 is seldom associated with bound repressors, whereas in contrast the active (H3K4me3) histone mark is overwhelmingly associated with TF binding. We hypothesise that during cellular differentiation and development, certain genes are silenced by repressive TFs that subsequently vacate the region. Catching such repressor TFs in the act of silencing via assays such as ChIP- Seq is thus a temporally challenging prospect. The use of inducible systems, epitope tags and alternative techniques may provide opportunities for detecting elusive ‘hit and run’ transcriptional silencing. Keywords hit and run, transcription factor, repressor, ChIP-Seq, transcriptional repression, transcriptional regulation, GATA1 Abbreviations ChIP - chromatin immunoprecipitation; ChIP-Seq - chromatin immunoprecipitation followed by high throughput sequencing; CUT&RUN - Cleavage Under Targets and Release Using Nuclease; FOG - Friend of GATA1; LacI - bacterial lac repressor; PIC – pre-initiation complex; PRC2 - polycomb repressive complex 2; REST/NRSF - RE1-Silencing Transcription Factor/Neuron-Restrictive Silence Factor; TALENs - transcription activator- like effector nucleases; TF - transcription factor; TSS - transcription start site; ZNFs - zinc finger nucleases Introduction Turning on the expression of a gene typically requires the binding of activator transcription factors (TFs) to regulatory DNA sequence elements, such as promoters and distal enhancers. TF binding subsequently leads to the recruitment of activating cofactors, histone modifying enzymes, and ultimately RNA polymerase II and the general TFs, which form the pre-initiation complex (PIC) [1]. Repeated rounds of transcriptional initiation are achieved by sustained occupancy or re-attendance by the activating TFs. Gene silencing, on the other hand, is different in that it is not necessarily dependent on the continuous residence of a sequence-specific repressor at a control element. This is an important distinction, because assays that detect genome-wide TF binding activity, such as ChIP-Seq (Chromatin Immunoprecipitation followed by high throughput sequencing), typically provide a static snapshot of occupancy precisely as it stands at the time-point of assay. For this reason, ChIP-Seq does not necessarily lend itself to the detection of some modes of transcriptional repression. This is an aspect that when overlooked, can skew our understanding of the gene regulatory mechanisms at play in a given cell type. Here we propose that activator TFs, and certain repressor TFs that operate via sustained or frequent binding of a nucleosome-depleted region, are readily amenable to detection by assays such as ChIP-Seq. In contrast, transcriptional repressors that elicit stable, long-term silencing by a ‘hit and run’ mechanism, will be more challenging to detect. This latter category will require dynamic, temporally controlled systems that allow such repressors to be ‘caught in the act’ during their window of silencing. In other words – repressors can act differently to activators. To use an analogy, in some cases, once the gene is locked down, the gaoler can sometimes, but not always, decide to throw away the key. In contrast, where gene activation is concerned, some sort of a key is likely to be evident every time the gene is transcribed. Figure 1. Models of transcriptional repression. a) Sustained TF binding represses the gene and is amenable to detection via ChIP or other TF binding assays. b) A ‘hit and run’ mechanism; The TF is bound initially and may recruit histone modifying enzymes/chromatin remodellers, which package the locus, preventing transcription and further TF binding. Binding is able to be detected initially but not once the locus is tightly packed (heterochromatin). Transcriptional repression and activation may occur through different mechanisms A classic example of a transcriptional repressor is the bacterial lac repressor (LacI) [2–4]. In the absence of lactose, it resides at the promoters of genes required for lactose metabolism and blocks engagement by RNA polymerase. Upon lactose exposure, LacI undergoes allosteric changes that abrogate its ability to bind these promoters, and subsequently, RNA polymerase is recruited and transcription commences. LacI is thus an example of a continuously binding repressor that renders the lac operon poised to dynamically respond to fluctuating metabolic requirements. Similarly, a textbook example of a mammalian transcriptional repressor is REST/NRSF (RE1- Silencing Transcription Factor/Neuron-Restrictive Silence Factor). REST resides at the control elements of neuronal genes in non-neuronal cells and represses their transcription [5–7]. In a very broad sense, REST thus silences gene expression in a similar fashion to LacI; it remains bound to its target genes for the duration of silencing, a characteristic that is amenable to ready detection. As such, REST is often invoked as a paradigmatic example of a mammalian transcriptional repressor. Yet how generally representative is REST of the mechanism of action of mammalian repressors? Do all sequence-specific transcriptional repressors remain bound to the control elements of the genes they silence throughout the life of the cell? Or rather, is it that we are prone to preferentially detect repressors that operate through this mode by assays such as ChIP- Seq? In somatic eukaryotic cells, only a fraction of the transcriptome is selectively expressed [8,9] and this in turn defines cell type identity. For any given cell type, thousands of genes are silent or repressed, a state that may be preserved through rounds of cell division or differentiation. Some of these may be continuously repressed by resident transcription factors akin to REST. It is tempting to speculate that these genes are in effect reversibly repressed, or poised to respond to specific stimuli, and that displacement of the resident TF could lead to their activation. Other genes, however, are stably repressed by general mechanisms of chromatin silencing. For instance, they may be silenced by local Polycomb-mediated H3K27 trimethylation and formation of facultative heterochromatin [10]. Alternatively, nucleosomal occlusion following remodeling may prevent the access of requisite activating TFs that have limited or no pioneering activity. Indeed, an important distinction to make is that in eukaryotes, as opposed to prokaryotes, the baseline state of chromatin is transcriptionally restrictive [11,12]. That is to say, in vivo, eukaryotic core promoters are intrinsically inert and are occluded by nucleosomes. Transcriptional initiation requires the coordinated action of transcriptional activators to displace nucleosomes and recruit the PIC. The ground state is thus one of transcriptional inactivity and the repressive capacity of nucleosomes alone or facultative heterochromatin can maintain gene silencing long after the departure of the repressor(s) that elicited the initial silencing. While sequence-specific repressors may be required to initially silence an active gene, they may not be essential for durable propagation of the repressed state. This mechanism of action is described as ‘hit and run’. These stable repression mechanisms are particularly important during development, enabling perpetuation of gene expression patterns through cell divisions and cellular differentiation. The patterning of Hox gene expression in Drosophila early embryogenesis is well studied and provides useful insights. During early embryogenesis, locally expressed gap gene products (transcriptional activators and repressors) directly bind to cis-acting regulatory regions in Hox genes and regulate transcription. The Hox genes that are initially repressed become stably repressed for the rest of development even when the gap repressors are no longer present. This repression is maintained by factors of the Polycomb group (PcG) [13–15]. Removal of most PcG proteins from proliferating cells causes de-repression. Interestingly, the resupply of these proteins within a certain window of time can cause re-repression [16]. This suggests that a mechanism beyond simple nucleosomal occlusion may be required for true long-term repression across multiple cell divisions or development. The maintainence of repression even after the initial transcriptional repressors are no longer present is consistent with a ‘hit and run’ mechanism. Where might one expect to detect evidence for ‘hit and run’ repressors? Many TFs appear to
Load more

Recommended publications
  • Peripheral T Cells Ets-1 Maintains IL-7 Receptor Expression In
    The Journal of Immunology Ets-1 Maintains IL-7 Receptor Expression in Peripheral T Cells Roland Grenningloh,*,† Tzong-Shyuan Tai,* Nicole Frahm,†,‡,1 Tomoyuki C. Hongo,‡ Adam T. Chicoine,‡ Christian Brander,†,‡,x,{ Daniel E. Kaufmann,†,‡,‖ and I-Cheng Ho*,† The expression of CD127, the IL-7–binding subunit of the IL-7 R, is tightly regulated during the development and activation of T cells and is reduced during chronic viral infection. However, the molecular mechanism regulating the dynamic expression of CD127 is still poorly understood. In this study, we report that the transcription factor Ets-1 is required for maintaining the expression of CD127 in murine peripheral T cells. Ets-1 binds to and activates the CD127 promoter, and its absence leads to reduced CD127 expression, attenuated IL-7 signaling, and impaired IL-7–dependent homeostatic proliferation of T cells. The expression of CD127 and Ets-1 is strongly correlated in human T cells. Both CD127 and Ets-1 expression are decreased in CD8+ T cells during HIV infection. In addition, HIV-associated loss of CD127 is only observed in Ets-1low effector memory and central memory but not in Ets-1high naive CD8+ T cells. Taken together, our data identify Ets-1 as a critical regulator of CD127 expression in T cells. The Journal of Immunology, 2011, 186: 969–976. nterleukin-7 signals are required for T cell development, GABPa or another Ets protein is responsible for maintaining maintaining the naive T cell pool, mounting proper primary CD127 expression in peripheral T cells is unknown. I responses, and inducing and maintaining CD4+ and CD8+ Ets-1 (E26 transformation-specific sequence) is the founding T cell memory (1–3).
    [Show full text]
  • Detection of Interacting Transcription Factors in Human Tissues Using
    Myšičková and Vingron BMC Genomics 2012, 13(Suppl 1):S2 http://www.biomedcentral.com/1471-2164/13/S1/S2 PROCEEDINGS Open Access Detection of interacting transcription factors in human tissues using predicted DNA binding affinity Alena Myšičková*, Martin Vingron From The Tenth Asia Pacific Bioinformatics Conference (APBC 2012) Melbourne, Australia. 17-19 January 2012 Abstract Background: Tissue-specific gene expression is generally regulated by combinatorial interactions among transcription factors (TFs) which bind to the DNA. Despite this known fact, previous discoveries of the mechanism that controls gene expression usually consider only a single TF. Results: We provide a prediction of interacting TFs in 22 human tissues based on their DNA-binding affinity in promoter regions. We analyze all possible pairs of 130 vertebrate TFs from the JASPAR database. First, all human promoter regions are scanned for single TF-DNA binding affinities with TRAP and for each TF a ranked list of all promoters ordered by the binding affinity is created. We then study the similarity of the ranked lists and detect candidates for TF-TF interaction by applying a partial independence test for multiway contingency tables. Our candidates are validated by both known protein-protein interactions (PPIs) and known gene regulation mechanisms in the selected tissue. We find that the known PPIs are significantly enriched in the groups of our predicted TF-TF interactions (2 and 7 times more common than expected by chance). In addition, the predicted interacting TFs for studied tissues (liver, muscle, hematopoietic stem cell) are supported in literature to be active regulators or to be expressed in the corresponding tissue.
    [Show full text]
  • Table S1. List of Proteins in the BAHD1 Interactome
    Table S1. List of proteins in the BAHD1 interactome BAHD1 nuclear partners found in this work yeast two-hybrid screen Name Description Function Reference (a) Chromatin adapters HP1α (CBX5) chromobox homolog 5 (HP1 alpha) Binds histone H3 methylated on lysine 9 and chromatin-associated proteins (20-23) HP1β (CBX1) chromobox homolog 1 (HP1 beta) Binds histone H3 methylated on lysine 9 and chromatin-associated proteins HP1γ (CBX3) chromobox homolog 3 (HP1 gamma) Binds histone H3 methylated on lysine 9 and chromatin-associated proteins MBD1 methyl-CpG binding domain protein 1 Binds methylated CpG dinucleotide and chromatin-associated proteins (22, 24-26) Chromatin modification enzymes CHD1 chromodomain helicase DNA binding protein 1 ATP-dependent chromatin remodeling activity (27-28) HDAC5 histone deacetylase 5 Histone deacetylase activity (23,29,30) SETDB1 (ESET;KMT1E) SET domain, bifurcated 1 Histone-lysine N-methyltransferase activity (31-34) Transcription factors GTF3C2 general transcription factor IIIC, polypeptide 2, beta 110kDa Required for RNA polymerase III-mediated transcription HEYL (Hey3) hairy/enhancer-of-split related with YRPW motif-like DNA-binding transcription factor with basic helix-loop-helix domain (35) KLF10 (TIEG1) Kruppel-like factor 10 DNA-binding transcription factor with C2H2 zinc finger domain (36) NR2F1 (COUP-TFI) nuclear receptor subfamily 2, group F, member 1 DNA-binding transcription factor with C4 type zinc finger domain (ligand-regulated) (36) PEG3 paternally expressed 3 DNA-binding transcription factor with
    [Show full text]
  • Mutations and Altered Expression of SERPINF1 in Patients with Familial Otosclerosis Joanna L
    Human Molecular Genetics, 2016, Vol. 25, No. 12 2393–2403 doi: 10.1093/hmg/ddw106 Advance Access Publication Date: 7 April 2016 Original Article ORIGINAL ARTICLE Mutations and altered expression of SERPINF1 in patients with familial otosclerosis Joanna L. Ziff1, Michael Crompton1, Harry R.F. Powell2, Jeremy A. Lavy2, Christopher P. Aldren3, Karen P. Steel4,†, Shakeel R. Saeed1,2 and Sally J. Dawson1,* 1UCL Ear Institute, University College London, London WC1X 8EE, UK, 2Royal National Throat Nose and Ear Hospital, London WC1X 8EE, UK, 3Department of ENT Surgery, The Princess Margaret Hospital, Windsor SL4 3SJ, UK and 4Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK *To whom correspondence should be addressed. Tel: þ44 2076798935; Email: [email protected] Abstract Otosclerosis is a relatively common heterogenous condition, characterized by abnormal bone remodelling in the otic capsule leading to fixation of the stapedial footplate and an associated conductive hearing loss. Although familial linkage and candidate gene association studies have been performed in recent years, little progress has been made in identifying disease- causing genes. Here, we used whole-exome sequencing in four families exhibiting dominantly inherited otosclerosis to identify 23 candidate variants (reduced to 9 after segregation analysis) for further investigation in a secondary cohort of 84 familial cases. Multiple mutations were found in the SERPINF1 (Serpin Peptidase Inhibitor, Clade F) gene which encodes PEDF (pigment epithelium-derived factor), a potent inhibitor of angiogenesis and known regulator of bone density. Six rare heterozygous SERPINF1 variants were found in seven patients in our familial otosclerosis cohort; three are missense mutations predicted to be deleterious to protein function.
    [Show full text]
  • Cellular Responses to Erbb-2 Overexpression in Human Mammary Luminal Epithelial Cells: Comparison of Mrna and Protein Expression
    British Journal of Cancer (2004) 90, 173 – 181 & 2004 Cancer Research UK All rights reserved 0007 – 0920/04 $25.00 www.bjcancer.com Cellular responses to ErbB-2 overexpression in human mammary luminal epithelial cells: comparison of mRNA and protein expression SL White1, S Gharbi1, MF Bertani1, H-L Chan1, MD Waterfield1 and JF Timms*,1 1 Ludwig Institute for Cancer Research, Wing 1.1, Cruciform Building, Gower Street, London WCIE 6BT, UK Microarray analysis offers a powerful tool for studying the mechanisms of cellular transformation, although the correlation between mRNA and protein expression is largely unknown. In this study, a microarray analysis was performed to compare transcription in response to overexpression of the ErbB-2 receptor tyrosine kinase in a model mammary luminal epithelial cell system, and in response to the ErbB-specific growth factor heregulin b1. We sought to validate mRNA changes by monitoring changes at the protein level using a parallel proteomics strategy, and report a surprisingly high correlation between transcription and translation for the subset of genes studied. We further characterised the identified targets and relate differential expression to changes in the biological properties of ErbB-2-overexpressing cells. We found differential regulation of several key cell cycle modulators, including cyclin D2, and downregulation of a large number of interferon-inducible genes, consistent with increased proliferation of the ErbB-2- overexpressing cells. Furthermore, differential expression of genes involved in extracellular matrix modelling and cellular adhesion was linked to altered adhesion of these cells. Finally, we provide evidence for enhanced autocrine activation of MAPK signalling and the AP-1 transcription complex.
    [Show full text]
  • Multiple Facets of Jund Gene Expression Are Atypical Among AP-1 Family Members
    Oncogene (2008) 27, 4757–4767 & 2008 Macmillan Publishers Limited All rights reserved 0950-9232/08 $30.00 www.nature.com/onc REVIEW Multiple facets of junD gene expression are atypical among AP-1 family members JM Hernandez1, DH Floyd2, KN Weilbaecher2, PL Green1,3 and K Boris-Lawrie1,3 1Department of Veterinary Biosciences and Center for Retrovirus Research, The Ohio State University, Columbus, OH, USA and 2Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St Louis, MO, USA and 3Department of Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA JunD is a versatile AP-1 transcription factor that can 2003; Milde-Langosch, 2005). The AP-1 component activate or repress a diverse collection of target genes. proteins are characterized structurally by their leucine- Precise control of junD expression and JunD protein– zipper dimerization motif and basic DNA-binding protein interactions modulate tumor angiogenesis, cellular domain. They can either activate or repress transcription differentiation, proliferation and apoptosis. Molecular and this versatile functional activity is dependent on the and clinical knowledge of two decades has revealed specific components of the dimeric complex and the that precise JunD activity is elaborated by interrelated cellular environment (Eferl and Wagner, 2003; Hess layers of constitutive transcriptional control, complex et al., 2004). AP-1 figures prominently in transcriptional post-transcriptional regulation and a collection of regulation of early response genes (reviewed by Jochum post-translational modifications and protein–protein et al., 2001; Mechta-Grigoriou et al., 2001; Eferl and interactions. The stakes are high, as inappropriate JunD Wagner, 2003).
    [Show full text]
  • Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model
    Downloaded from http://www.jimmunol.org/ by guest on September 25, 2021 T + is online at: average * The Journal of Immunology , 34 of which you can access for free at: 2016; 197:1477-1488; Prepublished online 1 July from submission to initial decision 4 weeks from acceptance to publication 2016; doi: 10.4049/jimmunol.1600589 http://www.jimmunol.org/content/197/4/1477 Molecular Profile of Tumor-Specific CD8 Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A. Waugh, Sonia M. Leach, Brandon L. Moore, Tullia C. Bruno, Jonathan D. Buhrman and Jill E. Slansky J Immunol cites 95 articles Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html http://www.jimmunol.org/content/suppl/2016/07/01/jimmunol.160058 9.DCSupplemental This article http://www.jimmunol.org/content/197/4/1477.full#ref-list-1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material References Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 25, 2021. The Journal of Immunology Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A.
    [Show full text]
  • 2017.08.28 Anne Barry-Reidy Thesis Final.Pdf
    REGULATION OF BOVINE β-DEFENSIN EXPRESSION THIS THESIS IS SUBMITTED TO THE UNIVERSITY OF DUBLIN FOR THE DEGREE OF DOCTOR OF PHILOSOPHY 2017 ANNE BARRY-REIDY SCHOOL OF BIOCHEMISTRY & IMMUNOLOGY TRINITY COLLEGE DUBLIN SUPERVISORS: PROF. CLIONA O’FARRELLY & DR. KIERAN MEADE TABLE OF CONTENTS DECLARATION ................................................................................................................................. vii ACKNOWLEDGEMENTS ................................................................................................................... viii ABBREVIATIONS ................................................................................................................................ix LIST OF FIGURES............................................................................................................................. xiii LIST OF TABLES .............................................................................................................................. xvii ABSTRACT ........................................................................................................................................xix Chapter 1 Introduction ........................................................................................................ 1 1.1 Antimicrobial/Host-defence peptides ..................................................................... 1 1.2 Defensins................................................................................................................. 1 1.3 β-defensins .............................................................................................................
    [Show full text]
  • 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.
    [Show full text]
  • SOX4-Mediated Repression of Specific Trnas Inhibits Proliferation of Human Glioblastoma Cells
    SOX4-mediated repression of specific tRNAs inhibits proliferation of human glioblastoma cells Jianjing Yanga,b,c, Derek K. Smithc,d, Haoqi Nia,b,c,KeWua,b, Dongdong Huanga,b, Sishi Pana,b,c, Adwait A. Sathee, Yu Tangc,d, Meng-Lu Liuc,d, Chao Xinge,f,g, Chun-Li Zhangc,d,1, and Qichuan Zhugea,b,1 aDepartment of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China 325000; bZhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China 325000; cDepartment of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390; dHamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; eMcDermott Center of Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390; fDepartment of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX 75390; and gDepartment of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390 Edited by S. Altman, Yale University, New Haven, CT, and approved February 5, 2020 (received for review November 15, 2019) Transfer RNAs (tRNAs) are products of RNA polymerase III (Pol III) indicates that tRNA expression may also be under cell state- and essential for mRNA translation and ultimately cell growth and dependent regulations (12–16). proliferation. Whether and how individual tRNA genes are specif- In this study, we performed a systematic analysis on how ically regulated is not clear. Here, we report that SOX4, a well- NGN2/SOX4-mediated cell-fate reprogramming leads to cell known Pol II-dependent transcription factor that is critical for neuro- cycle exit of human glioblastoma cells.
    [Show full text]
  • 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.
    [Show full text]
  • 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).
    [Show full text]