DOCSLIB.ORG

A Fine Balance: Epigenetic Control of Cellular Quiescence by the Tumor Suppressor PRDM2/RIZ at a Bivalent Domain in the Cyclin a Gene

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A Fine Balance: Epigenetic Control of Cellular Quiescence by the Tumor Suppressor PRDM2/RIZ at a Bivalent Domain in the Cyclin a Gene University of Southern Denmark A fine balance epigenetic control of cellular quiescence by the tumor suppressor PRDM2/RIZ at a bivalent domain in the cyclin a gene Cheedipudi, Sirisha; Puri, Deepika; Saleh, Amena; Gala, Hardik P; Rumman, Mohammed; Pillai, Malini S; Sreenivas, Prethish; Arora, Reety; Sellathurai, Jeeva; Schrøder, Henrik Daa; Mishra, Rakesh K; Dhawan, Jyotsna Published in: Nucleic Acids Research DOI: 10.1093/nar/gkv567 Publication date: 2015 Document version: Final published version Document license: CC BY-NC Citation for pulished version (APA): Cheedipudi, S., Puri, D., Saleh, A., Gala, H. P., Rumman, M., Pillai, M. S., Sreenivas, P., Arora, R., Sellathurai, J., Schrøder, H. D., Mishra, R. K., & Dhawan, J. (2015). A fine balance: epigenetic control of cellular quiescence by the tumor suppressor PRDM2/RIZ at a bivalent domain in the cyclin a gene. Nucleic Acids Research, 43(13), 6236-6256. https://doi.org/10.1093/nar/gkv567 Go to publication entry in University of Southern Denmark's Research Portal Terms of use This work is brought to you by the University of Southern Denmark. Unless otherwise specified it has been shared according to the terms for self-archiving. If no other license is stated, these terms apply: • You may download this work for personal use only. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying this open access version If you believe that this document breaches copyright please contact us providing details and we will investigate your claim. Please direct all enquiries to [email protected] Download date: 05. Oct. 2021 6236–6256 Nucleic Acids Research, 2015, Vol. 43, No. 13 Published online 3 June 2015 doi: 10.1093/nar/gkv567 A fine balance: epigenetic control of cellular quiescence by the tumor suppressor PRDM2/RIZ at a bivalent domain in the cyclin a gene Sirisha Cheedipudi1,2,4,†, Deepika Puri1,5,†, Amena Saleh1,6, Hardik P. Gala1,2, Mohammed Rumman1,6, Malini S. Pillai1, Prethish Sreenivas1,2, Reety Arora1, Jeeva Sellathurai3, Henrik Daa Schrøder3, Rakesh K. Mishra2 and Jyotsna Dhawan1,2,* 1Institute for Stem Cell Biology and Regenerative Medicine, National Center for Biological Sciences, GKVK Post, Bellary Road, Bangalore 560065, India, 2Council of Scientific and Industrial Research-Centre for Cellular and Molecular Biology, Hyderabad 500 007, India, 3Institute of Clinical Research, SDU Muscle Research Cluster (SMRC), University of Southern Denmark, Odense 5000 C, Denmark, 4Max Planck Institute for Heart and Lung Research, Bad Nauheim 61231, Germany, 5Max Planck Institute of Immunobiology and Epigenetics, Freiburg D-79108, Germany and 6Manipal University, Manipal 576104 India Received October 25, 2014; Revised April 23, 2015; Accepted May 19, 2015 ABSTRACT preserves key functions of the quiescent state, with implications for stem cell self-renewal. Adult stem cell quiescence is critical to ensure re- generation while minimizing tumorigenesis. Epige- netic regulation contributes to cell cycle control and INTRODUCTION differentiation, but few regulators of the chromatin Epigenetic regulatory mechanisms play a crucial role in cell state in quiescent cells are known. Here we report fate decisions, whereby global and local controls are im- that the tumor suppressor PRDM2/RIZ, an H3K9 posed on chromatin and result in distinct transcriptional methyltransferase, is enriched in quiescent muscle programs. The epi-genome of pluripotent embryonic stem stem cells in vivo and controls reversible quiescence cells (ESC) is highly permissive, accommodating both self- in cultured myoblasts. We find that PRDM2 asso- renewal and broad differentiation potential. During devel- opment, chromatin configuration becomes progressively re- ciates with >4400 promoters in G0 myoblasts, 55% of which are also marked with H3K9me2 and enriched strictive as cells commit and differentiate into specific lin- eages. Regulation at the level of chromatin is emerging as a for myogenic, cell cycle and developmental regula- primary determinant in the establishment and maintenance tors. Knockdown of PRDM2 alters histone methyla- of heritable gene expression patterns (1–4). tion at key promoters such as Myogenin and Cy- The global chromatin landscape is controlled by a hier- clinA2 (CCNA2), and subverts the quiescence pro- archy of mechanisms, of which regulation at the level of gram via global de-repression of myogenesis, and the basic unit, the nucleosome, is best understood. Inter- hyper-repression of the cell cycle. Further, PRDM2 actions of the core nucleosomal histones (H2A, H2B, H3 acts upstream of the repressive PRC2 complex in and H4) leave their N terminal tails accessible to a range G0. We identify a novel G0-specific bivalent chro- of post-translational modifications that are deposited, read matin domain in the CCNA2 locus. PRDM2 pro- or erased by a wide variety of chromatin modifying en- tein interacts with the PRC2 protein EZH2 and reg- zymes, altering the packaging of DNA. Dynamic changes ulates its association with the bivalent domain in in histone modifications can therefore also alter DNA- transcription factor interactions, and may either accom- the CCNA2 gene. Our results suggest that induc- pany or precede transcriptional activation or repression. tion of PRDM2 in G0 ensures that two antagonis- Thus, the ‘histone code’ embodies gene regulatory infor- tic programs––myogenesis and the cell cycle––while mation that is embedded in complex cell type- and cell stalled, are poised for reactivation. Together, these state-specific combinations of histone modifications (5). results indicate that epigenetic regulation by PRDM2 Typically, in addition to the requisite RNA polymerase II (pol II) binding, transcription activation correlates with tri- *To whom correspondence should be addressed. Tel: +91-80-23666016; Fax: +91-80-2363-6662; Email: [email protected] †These authors contributed equally to the paper as first authors. C The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] Nucleic Acids Research, 2015, Vol. 43, No. 13 6237 methylation of lysine 4 of H3 (H3K4me3), together with hi- posit H3K27me3 marks and permanently silence cell cycle stone acetylation (H3K9Ac). By contrast, transcription re- genes during differentiation (26). In human cells, p130 and pression often involves tri-methylation of lysine 27 of H3 E2F factors associate with MuvB-like proteins in G0, form- (H3K27me3) and di-or tri-methylation of lysine 9 of H3 ing the DREAM complex that is involved in repression of (H3K9me2/3), through the recruitment of repressive pro- cell cycle genes (27) and in Drosophila, dREAM is impli- tein complexes. cated in repression of a wide variety of developmental genes Heritability of epigenetic information has to meet the (28). challenge of chromatin disassembly and reassembly dur- In ESC, cell fate loci are located in ‘bivalent domains’ ing DNA synthesis, necessitating cellular memory mecha- (marked by both H3K27me3 and H3K4me3), in a tran- nisms, particularly in adult stem cells (ASC). Adult tissues scriptionally repressed state poised for activation (29–31). are comprised of cells in distinct non-proliferating states Lineage commitment correlates with a shift to unique mark- with distinct functions. In skeletal muscle, differentiated ing by tri-methylation of either H3K27 (silencing) or H3K4 myofibers are permanently arrested (post-mitotic), buta (activation), which underlies and reinforces cell fate choices. rare population of satellite stem cells enters an alternate ASC are also thought to maintain a chromatin configura- cell cycle exit (quiescence or G0), retaining the option to tion permissive to a (restricted) set of alternate fates (4). reactivate and repair damage (reviewed in (6)). Recent evi- Recent reports describe bivalent domains in ASC including dence suggests that rather than a state of passive hiberna- muscle SCs (32), but mechanisms of poising are unexplored. tion entered when nutrients or mitogens are limiting, the Using genome-wide location analysis, transcriptome quiescence program is actively regulated at transcriptional analysis and RNAi, we now report that a single regulator, (7–10) and epigenetic (11–13) levels. Deregulation of quies- an H3K9 methyl transferase PRDM2, is induced in quies- cence may underlie both tumorigenesis (failure to enter G0 cence and binds to thousands of promoters in quiescent my- leading to uncontrolled proliferation), as well as degenera- oblasts, over half of which are also marked by the repressive tive disease (failure to exit G0 leading to loss of progenitor H3K9me2 mark. PRDM2 acts in two modes on differen- function), necessitating an understanding of mechanisms tiation versus cell cycle target genes––while it represses the that control this arrested state. activity of the Myogenin promoter in quiescence, this epige- The mechanisms by which stem cells achieve cellular netic regulator also controls association of the PRC2 com- memory to keep specific regions of their genome repressed plex at a novel G0-specific bivalent domain in the CCNA2 but ready to respond to regenerative
Load more

Recommended publications
  • 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]
  • Table S1 the Four Gene Sets Derived from Gene Expression Profiles of Escs and Differentiated Cells
    Table S1 The four gene sets derived from gene expression profiles of ESCs and differentiated cells Uniform High Uniform Low ES Up ES Down EntrezID GeneSymbol EntrezID GeneSymbol EntrezID GeneSymbol EntrezID GeneSymbol 269261 Rpl12 11354 Abpa 68239 Krt42 15132 Hbb-bh1 67891 Rpl4 11537 Cfd 26380 Esrrb 15126 Hba-x 55949 Eef1b2 11698 Ambn 73703 Dppa2 15111 Hand2 18148 Npm1 11730 Ang3 67374 Jam2 65255 Asb4 67427 Rps20 11731 Ang2 22702 Zfp42 17292 Mesp1 15481 Hspa8 11807 Apoa2 58865 Tdh 19737 Rgs5 100041686 LOC100041686 11814 Apoc3 26388 Ifi202b 225518 Prdm6 11983 Atpif1 11945 Atp4b 11614 Nr0b1 20378 Frzb 19241 Tmsb4x 12007 Azgp1 76815 Calcoco2 12767 Cxcr4 20116 Rps8 12044 Bcl2a1a 219132 D14Ertd668e 103889 Hoxb2 20103 Rps5 12047 Bcl2a1d 381411 Gm1967 17701 Msx1 14694 Gnb2l1 12049 Bcl2l10 20899 Stra8 23796 Aplnr 19941 Rpl26 12096 Bglap1 78625 1700061G19Rik 12627 Cfc1 12070 Ngfrap1 12097 Bglap2 21816 Tgm1 12622 Cer1 19989 Rpl7 12267 C3ar1 67405 Nts 21385 Tbx2 19896 Rpl10a 12279 C9 435337 EG435337 56720 Tdo2 20044 Rps14 12391 Cav3 545913 Zscan4d 16869 Lhx1 19175 Psmb6 12409 Cbr2 244448 Triml1 22253 Unc5c 22627 Ywhae 12477 Ctla4 69134 2200001I15Rik 14174 Fgf3 19951 Rpl32 12523 Cd84 66065 Hsd17b14 16542 Kdr 66152 1110020P15Rik 12524 Cd86 81879 Tcfcp2l1 15122 Hba-a1 66489 Rpl35 12640 Cga 17907 Mylpf 15414 Hoxb6 15519 Hsp90aa1 12642 Ch25h 26424 Nr5a2 210530 Leprel1 66483 Rpl36al 12655 Chi3l3 83560 Tex14 12338 Capn6 27370 Rps26 12796 Camp 17450 Morc1 20671 Sox17 66576 Uqcrh 12869 Cox8b 79455 Pdcl2 20613 Snai1 22154 Tubb5 12959 Cryba4 231821 Centa1 17897
    [Show full text]
  • Genetic Variability in the Italian Heavy Draught Horse from Pedigree Data and Genomic Information
    Supplementary material for manuscript: Genetic variability in the Italian Heavy Draught Horse from pedigree data and genomic information. Enrico Mancin†, Michela Ablondi†, Roberto Mantovani*, Giuseppe Pigozzi, Alberto Sabbioni and Cristina Sartori ** Correspondence: [email protected] † These two Authors equally contributed to the work Supplementary Figure S1. Mares and foal of Italian Heavy Draught Horse (IHDH; courtesy of Cinzia Stoppa) Supplementary Figure S2. Number of Equivalent Generations (EqGen; above) and pedigree completeness (PC; below) over years in Italian Heavy Draught Horse population. Supplementary Table S1. Descriptive statistics of homozygosity (observed: Ho_obs; expected: Ho_exp; total: Ho_tot) in 267 genotyped individuals of Italian Heavy Draught Horse based on the number of homozygous genotypes. Parameter Mean SD Min Max Ho_obs 35,630.3 500.7 34,291 38,013 Ho_exp 35,707.8 64.0 35,010 35,740 Ho_tot 50,674.5 93.8 49,638 50,714 1 Definitions of the methods for inbreeding are in the text. Supplementary Figure S3. Values of BIC obtained by analyzing values of K from 1 to 10, corresponding on the same amount of clusters defining the proportion of ancestry in the 267 genotyped individuals. Supplementary Table S2. Estimation of genomic effective population size (Ne) traced back to 18 generations ago (Gen. ago). The linkage disequilibrium estimation, adjusted for sampling bias was also included (LD_r2), as well as the relative standard deviation (SD(LD_r2)). Gen. ago Ne LD_r2 SD(LD_r2) 1 100 0.009 0.014 2 108 0.011 0.018 3 118 0.015 0.024 4 126 0.017 0.028 5 134 0.019 0.031 6 143 0.021 0.034 7 156 0.023 0.038 9 173 0.026 0.041 11 189 0.029 0.046 14 213 0.032 0.052 18 241 0.036 0.058 Supplementary Table S3.
    [Show full text]
  • Roles of Id3 and IL-13 in a Mouse Model of Autoimmune Exocrinopathy
    Roles of Id3 and IL-13 in a Mouse Model of Autoimmune Exocrinopathy by Ian Lawrence Belle Department of Immunology Duke University Date:_______________________ Approved: ___________________________ Yuan Zhuang, Supervisor ___________________________ Michael Krangel, Chair ___________________________ Qi-jing Li ___________________________ Richard Lee Reinhardt ___________________________ Arno Greenleaf Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Immunology in the Graduate School of Duke University 2015 ABSTRACT Roles of Id3 and IL-13 in a Mouse Model of Autoimmune Exocrinopathy by Ian Lawrence Belle Department of Immunology Duke University Date:_______________________ Approved: ___________________________ Yuan Zhuang, Supervisor ___________________________ Michael Krangel, Chair ___________________________ Qi-jing Li ___________________________ Richard Lee Reinhardt ___________________________ Arno Greenleaf An abstract of a dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Immunology in the Graduate School of Duke University 2015 Copyright by Ian Lawrence Belle 2015 Abstract Within the field of immunology, the existence of autoimmune diseases presents a unique set of challenges. The immune system typically protects the host by identifying foreign pathogens and mounting an appropriate response to eliminate them. Great strides have been made in understanding how foreign pathogens are identified and responded to, leading to the development of powerful immunological tools, such as vaccines and a myriad of models used to study infectious diseases and processes. However, it is occasionally possible for host tissues themselves to be inappropriately identified as foreign, prompting an immune response that attempts to eliminate the host tissue. The immune system has processes in place, referred to as selection, designed to prevent the development of cells capable of recognizing the self as foreign.
    [Show full text]
  • Homeobox Gene Expression Profile in Human Hematopoietic Multipotent
    Leukemia (2003) 17, 1157–1163 & 2003 Nature Publishing Group All rights reserved 0887-6924/03 $25.00 www.nature.com/leu Homeobox gene expression profile in human hematopoietic multipotent stem cells and T-cell progenitors: implications for human T-cell development T Taghon1, K Thys1, M De Smedt1, F Weerkamp2, FJT Staal2, J Plum1 and G Leclercq1 1Department of Clinical Chemistry, Microbiology and Immunology, Ghent University Hospital, Ghent, Belgium; and 2Department of Immunology, Erasmus Medical Center, Rotterdam, The Netherlands Class I homeobox (HOX) genes comprise a large family of implicated in this transformation proces.14 The HOX-C locus transcription factors that have been implicated in normal and has been primarily implicated in lymphomas.15 malignant hematopoiesis. However, data on their expression or function during T-cell development is limited. Using degener- Hematopoietic cells are derived from stem cells that reside in ated RT-PCR and Affymetrix microarray analysis, we analyzed fetal liver (FL) in the embryo and in the adult bone marrow the expression pattern of this gene family in human multipotent (ABM), which have the unique ability to self-renew and thereby stem cells from fetal liver (FL) and adult bone marrow (ABM), provide a life-long supply of blood cells. T lymphocytes are a and in T-cell progenitors from child thymus. We show that FL specific type of hematopoietic cells that play a major role in the and ABM stem cells are similar in terms of HOX gene immune system. They develop through a well-defined order of expression, but significant differences were observed between differentiation steps in the thymus.16 Several transcription these two cell types and child thymocytes.
    [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]
  • Based Mechanism Study on the Beneficial Effects of Vitamin D
    www.nature.com/scientificreports OPEN Network Systems Pharmacology- Based Mechanism Study on the Benefcial Efects of Vitamin D against Psychosis in Alzheimer’s Disease Peihao Fan1, Xiguang Qi1, Robert A. Sweet2,3* & Lirong Wang1* Alzheimer’s disease (AD) is a chronic neurodegenerative disease with signifcant fnancial costs and negative impacts on quality of life. Psychotic symptoms, i.e., the presence of delusions and/ or hallucinations, is a frequent complication of AD. About 50% of AD patients will develop psychotic symptoms (AD with Psychosis, or AD + P) and these patients will experience an even more rapid cognitive decline than AD patients without psychosis (AD-P). In a previous analysis on medication records of 776 AD patients, we had shown that use of Vitamin D was associated with delayed time to psychosis in AD patients and Vitamin D was used more by AD-P than AD + P patients. To explore the potential molecular mechanism behind our fndings, we applied systems pharmacology approaches to investigate the crosstalk between AD and psychosis. Specifcally, we built protein-protein interaction (PPI) networks with proteins encoded by AD- and psychosis-related genes and Vitamin D-perturbed genes. Using network analysis we identifed several high-impact genes, including NOTCH4, COMT, CACNA1C and DRD3 which are related to calcium homeostasis. The new fndings highlight the key role of calcium-related signaling pathways in AD + P development and may provide a new direction and facilitate hypothesis generation for future drug development. Alzheimer’s disease (AD) is a chronic neurodegenerative disease commonly seen in the aging population, and the presence of AD is responsible for a signifcant decrease in the quality of life1.
    [Show full text]
  • The E–Id Protein Axis Modulates the Activities of the PI3K–AKT–Mtorc1
    Downloaded from genesdev.cshlp.org on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press The E–Id protein axis modulates the activities of the PI3K–AKT–mTORC1– Hif1a and c-myc/p19Arf pathways to suppress innate variant TFH cell development, thymocyte expansion, and lymphomagenesis Masaki Miyazaki,1,8 Kazuko Miyazaki,1,8 Shuwen Chen,1 Vivek Chandra,1 Keisuke Wagatsuma,2 Yasutoshi Agata,2 Hans-Reimer Rodewald,3 Rintaro Saito,4 Aaron N. Chang,5 Nissi Varki,6 Hiroshi Kawamoto,7 and Cornelis Murre1 1Department of Molecular Biology, University of California at San Diego, La Jolla, California 92093, USA; 2Department of Biochemistry and Molecular Biology, Shiga University of Medical School, Shiga 520-2192, Japan; 3Division of Cellular Immunology, German Cancer Research Center, D-69120 Heidelberg, Germany; 4Department of Medicine, University of California at San Diego, La Jolla, California 92093, USA; 5Center for Computational Biology, Institute for Genomic Medicine, University of California at San Diego, La Jolla, California 92093, USA; 6Department of Pathology, University of California at San Diego, La Jolla, California 92093, USA; 7Department of Immunology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan It is now well established that the E and Id protein axis regulates multiple steps in lymphocyte development. However, it remains unknown how E and Id proteins mechanistically enforce and maintain the naı¨ve T-cell fate. Here we show that Id2 and Id3 suppressed the development and expansion of innate variant follicular helper T (TFH) cells. Innate variant TFH cells required major histocompatibility complex (MHC) class I-like signaling and were associated with germinal center B cells.
    [Show full text]
  • Animal Cells Anterior Epidermis Anterior Epidermis A-Neural
    Anterior Epidermis Anterior Epidermis KH2012 TF common name Log2FC -Log(pvalue) Log2FC -Log(pvalue) DE in Imai Matched PWM PWM Cluster KH2012 TF common name Log2FC -Log(pvalue) Log2FC -Log(pvalue) DE in Imai Matched PWM PWM Cluster gene model Sibling Cluster Sibling Cluster Parent Cluster Parent Cluster z-score z-score gene model Sibling Cluster Sibling Cluster Parent Cluster Parent Cluster z-score z-score KH2012:KH.C11.485 Irx-B 1.0982 127.5106 0.9210 342.5323 Yes No PWM Hits No PWM Hits KH2012:KH.C1.159 E(spl)/hairy-a 1.3445 65.6302 0.6908 14.3413 Not Analyzed -15.2125 No PWM Hits KH2012:KH.L39.1 FoxH-b 0.6677 45.8148 1.1074 185.2909 No -3.3335 5.2695 KH2012:KH.C1.99 SoxB1 1.2482 73.2413 0.3331 9.3534 Not Analyzed No PWM match No PWM match KH2012:KH.C1.159 E(spl)/hairy-a 0.6233 47.2239 0.4339 77.0192 Yes -10.496 No PWM Hits KH2012:KH.C11.485 Irx-B 1.2355 72.8859 0.1608 0.0137 Not Analyzed No PWM Hits No PWM Hits KH2012:KH.C7.43 AP-2-like2 0.4991 31.7939 0.4775 68.8091 Yes 10.551 21.586 KH2012:KH.C1.1016 GCNF 0.8556 36.2030 1.3828 100.1236 Not Analyzed No PWM match No PWM match KH2012:KH.C1.99 SoxB1 0.4913 33.7808 0.3406 39.0890 No No PWM match No PWM match KH2012:KH.L108.4 CREB/ATF-a 0.6859 37.8207 0.3453 15.8154 Not Analyzed 6.405 8.6245 KH2012:KH.C7.157 Emc 0.4139 19.2080 1.1001 173.3024 Yes No PWM match No PWM match KH2012:KH.S164.12 SoxB2 0.6194 22.8414 0.6433 35.7335 Not Analyzed 8.722 17.405 KH2012:KH.C4.366 ERF2 -0.4878 -32.3767 -0.1770 -0.2316 No -10.324 9.7885 KH2012:KH.L4.17 Zinc Finger (C2H2)-18 0.6166 24.8925 0.2386 5.3130
    [Show full text]
  • Genome-Wide DNA Methylation Analysis of KRAS Mutant Cell Lines Ben Yi Tew1,5, Joel K
    www.nature.com/scientificreports OPEN Genome-wide DNA methylation analysis of KRAS mutant cell lines Ben Yi Tew1,5, Joel K. Durand2,5, Kirsten L. Bryant2, Tikvah K. Hayes2, Sen Peng3, Nhan L. Tran4, Gerald C. Gooden1, David N. Buckley1, Channing J. Der2, Albert S. Baldwin2 ✉ & Bodour Salhia1 ✉ Oncogenic RAS mutations are associated with DNA methylation changes that alter gene expression to drive cancer. Recent studies suggest that DNA methylation changes may be stochastic in nature, while other groups propose distinct signaling pathways responsible for aberrant methylation. Better understanding of DNA methylation events associated with oncogenic KRAS expression could enhance therapeutic approaches. Here we analyzed the basal CpG methylation of 11 KRAS-mutant and dependent pancreatic cancer cell lines and observed strikingly similar methylation patterns. KRAS knockdown resulted in unique methylation changes with limited overlap between each cell line. In KRAS-mutant Pa16C pancreatic cancer cells, while KRAS knockdown resulted in over 8,000 diferentially methylated (DM) CpGs, treatment with the ERK1/2-selective inhibitor SCH772984 showed less than 40 DM CpGs, suggesting that ERK is not a broadly active driver of KRAS-associated DNA methylation. KRAS G12V overexpression in an isogenic lung model reveals >50,600 DM CpGs compared to non-transformed controls. In lung and pancreatic cells, gene ontology analyses of DM promoters show an enrichment for genes involved in diferentiation and development. Taken all together, KRAS-mediated DNA methylation are stochastic and independent of canonical downstream efector signaling. These epigenetically altered genes associated with KRAS expression could represent potential therapeutic targets in KRAS-driven cancer. Activating KRAS mutations can be found in nearly 25 percent of all cancers1.
    [Show full text]
  • 1 AGING Supplementary Table 2
    SUPPLEMENTARY TABLES Supplementary Table 1. Details of the eight domain chains of KIAA0101. Serial IDENTITY MAX IN COMP- INTERFACE ID POSITION RESOLUTION EXPERIMENT TYPE number START STOP SCORE IDENTITY LEX WITH CAVITY A 4D2G_D 52 - 69 52 69 100 100 2.65 Å PCNA X-RAY DIFFRACTION √ B 4D2G_E 52 - 69 52 69 100 100 2.65 Å PCNA X-RAY DIFFRACTION √ C 6EHT_D 52 - 71 52 71 100 100 3.2Å PCNA X-RAY DIFFRACTION √ D 6EHT_E 52 - 71 52 71 100 100 3.2Å PCNA X-RAY DIFFRACTION √ E 6GWS_D 41-72 41 72 100 100 3.2Å PCNA X-RAY DIFFRACTION √ F 6GWS_E 41-72 41 72 100 100 2.9Å PCNA X-RAY DIFFRACTION √ G 6GWS_F 41-72 41 72 100 100 2.9Å PCNA X-RAY DIFFRACTION √ H 6IIW_B 2-11 2 11 100 100 1.699Å UHRF1 X-RAY DIFFRACTION √ www.aging-us.com 1 AGING Supplementary Table 2. Significantly enriched gene ontology (GO) annotations (cellular components) of KIAA0101 in lung adenocarcinoma (LinkedOmics). Leading Description FDR Leading Edge Gene EdgeNum RAD51, SPC25, CCNB1, BIRC5, NCAPG, ZWINT, MAD2L1, SKA3, NUF2, BUB1B, CENPA, SKA1, AURKB, NEK2, CENPW, HJURP, NDC80, CDCA5, NCAPH, BUB1, ZWILCH, CENPK, KIF2C, AURKA, CENPN, TOP2A, CENPM, PLK1, ERCC6L, CDT1, CHEK1, SPAG5, CENPH, condensed 66 0 SPC24, NUP37, BLM, CENPE, BUB3, CDK2, FANCD2, CENPO, CENPF, BRCA1, DSN1, chromosome MKI67, NCAPG2, H2AFX, HMGB2, SUV39H1, CBX3, TUBG1, KNTC1, PPP1CC, SMC2, BANF1, NCAPD2, SKA2, NUP107, BRCA2, NUP85, ITGB3BP, SYCE2, TOPBP1, DMC1, SMC4, INCENP. RAD51, OIP5, CDK1, SPC25, CCNB1, BIRC5, NCAPG, ZWINT, MAD2L1, SKA3, NUF2, BUB1B, CENPA, SKA1, AURKB, NEK2, ESCO2, CENPW, HJURP, TTK, NDC80, CDCA5, BUB1, ZWILCH, CENPK, KIF2C, AURKA, DSCC1, CENPN, CDCA8, CENPM, PLK1, MCM6, ERCC6L, CDT1, HELLS, CHEK1, SPAG5, CENPH, PCNA, SPC24, CENPI, NUP37, FEN1, chromosomal 94 0 CENPL, BLM, KIF18A, CENPE, MCM4, BUB3, SUV39H2, MCM2, CDK2, PIF1, DNA2, region CENPO, CENPF, CHEK2, DSN1, H2AFX, MCM7, SUV39H1, MTBP, CBX3, RECQL4, KNTC1, PPP1CC, CENPP, CENPQ, PTGES3, NCAPD2, DYNLL1, SKA2, HAT1, NUP107, MCM5, MCM3, MSH2, BRCA2, NUP85, SSB, ITGB3BP, DMC1, INCENP, THOC3, XPO1, APEX1, XRCC5, KIF22, DCLRE1A, SEH1L, XRCC3, NSMCE2, RAD21.
    [Show full text]
  • Homeobox A10 Promotes the Proliferation and Invasion of Bladder Cancer Cells Via Regulation of Matrix Metalloproteinase‑3
    ONCOLOGY LETTERS 18: 49-56, 2019 Homeobox A10 promotes the proliferation and invasion of bladder cancer cells via regulation of matrix metalloproteinase‑3 CHUNLEI LIU1*, MINGZHU GE2*, JUN MA1*, YANHUI ZHANG1, YANHUI ZHAO1 and TAO CUI1 Departments of 1Urology and 2Ultrasound, Qingdao Central Hospital, Qingdao, Shandong 266042, P.R. China Received February 9, 2018; Accepted January 31, 2019 DOI: 10.3892/ol.2019.10312 Abstract. Homeobox A10 (HOXA10) belongs to the family Smoking and obesity are risk factors for BC (2), and genetic of HOX genes, which are closely connected with embryonic mutations and abnormal protein expression serve important development and serve important roles in various tumors. roles in the genesis, development and progression of BC (4). However, the role of HOXA10 in bladder cancer (BC) remains Therefore, exploring new anomalous molecules involved in unclear. In the present study, the role of HOXA10 in BC and the development of BC may advance the understanding of the underlying mechanisms by which it promotes the disease the mechanisms behind this disease and contribute to the progression were investigated. Immunohistochemical analysis improvement of treatment strategies. demonstrated that the expression of the HOXA10 protein Homeobox A10 (HOXA10) belongs to the family of HOX was significantly higher in BC tissues as compared with that genes, which are classified into four subgroups, namely HOX in adjacent normal tissues. Subsequent statistical analysis A-D (5), and are closely connected with embryonic develop- revealed that upregulation of HOXA10 was significantly ment (6). HOXA10 encodes a DNA-binding transcription factor associated with the pathological grade and clinical stage of that serves vital roles in regulating gene expression, viability BC patients.
    [Show full text]