DOCSLIB.ORG

Mechanisms of Aryl Hydrocarbon Receptor-Mediated Regulation of Gene Expression and the Cell Cycle

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Mechanisms of Aryl Hydrocarbon Receptor-Mediated Regulation of Gene Expression and the Cell Cycle UNIVERSITY OF CINCINNATI Date:___________________ I, _________________________________________________________, hereby submit this work as part of the requirements for the degree of: in: It is entitled: This work and its defense approved by: Chair: _______________________________ _______________________________ _______________________________ _______________________________ _______________________________ Mechanisms of Aryl Hydrocarbon Receptor-Mediated Regulation of Gene Expression and the Cell Cycle A dissertation submitted to the Division of Research and Advanced Studies of the University of Cincinnati In partial fulfillment of the requirements for the degree of DOCTORATE OF PHILOSOPHY (Ph.D.) In the Department of Environmental Health of the College of Medicine November 28, 2006 by Jennifer L. Marlowe B.S., Miami University, 1999 Committee Chair: Alvaro Puga, Ph.D. Professor Department of Environmental Health University of Cincinnati Committee: Dr. Timothy Dalton Dr. Mary Beth Genter Dr. Erik Knudsen Dr. Ying Xia The focus of this dissertation is the discovery of novel mechanisms and pathways of gene regulation by the aryl hydrocarbon receptor (AHR), primarily regarding the role of this protein in modulating cell cycle progression. The AHR is a member of the PAS (Per-Arnt-Sim) superfamily of receptors, which mediate responses to environmental stresses such as hypoxia and circadian rhythm, and control basic physiologic processes like vascular development, learning, and neurogenesis. The AHR protein was discovered by virtue of its high affinity interaction with the persistent environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and is now known as the primary mediator of the toxic effects of this and hundreds of other HAH and PAH ligands. The mechanisms by which the AHR acts to mediate toxicity of these compounds include the activity of the AHR as a potent transcriptional activator. The ligand-bound AHR, with its dimerization-binding partner ARNT, upregulates the expression of a battery of genes that function in the metabolism of PAH and HAH compounds. However, the diversity of toxic responses mediated by compounds such as TCDD are not adequately explained by the expression of this battery of genes. One of the primary roles of the AHR, both from a physiological and toxicological standpoint, is the control of cell cycle progression. The AHR may affect cell proliferation, differentiation, or apoptosis depending on the cell type examined, and the mechanisms of these effects remain unclear. Literally hundreds of genes have been implicated as being regulated either directly or indirectly by the AHR, and many of these genes are related to aspects of cell cycle control. The goal of this dissertation is to explore mechanisms by which the AHR modulates the cell cycle through the investigation of novel gene targets of the receptor. Chapter 2 summarizes the current body of knowledge regarding the AHR, its ligands, and perturbations of the cell cycle. Chapter 3 investigates a mechanism whereby the AHR is able to repress the expression of specific cell cycle-regulated genes through its interaction with iii the retinoblastoma protein, a tumor suppressor and major component of the G1/S checkpoint control mechanism. Chapter 4 explores an interaction between the AHR and E2F proteins, also major regulatory components of S-phase progression and DNA replication, and the constitutive activity of the AHR in maintaining basal expression levels of a large number of E2F-regulated genes. Finally, Chapter 5 outlines the identification of novel promoter targets of the AHR using chromatin immunoprecipitation and promoter tiling arrays. The results presented throughout this work show the diversity of AHR functions related both to toxicological endpoints and normal cell physiology, and illustrate the ability of this important transcription factor to regulate the expression of a large number of genes by a variety of distinctive mechanisms. iv v Acknowledgements My sincerest gratitude goes to Dr. Alvaro Puga for inviting me to join his lab as a graduate student, after hiring me as a technician with almost no experience in molecular or cell biology. He believed in me all those years ago, and the decision I made to complete my thesis work in his lab has led me to follow paths I only dreamed of going down before. I have learned almost everything I know about research, and a lot about life as well, from Alvaro, and am forever grateful for both the personal and professional experience of working in his lab. I am indebted to all of the members of my dissertation committee for their dedication, insight, and criticisms that have helped to produce this thesis. Many thanks to Drs. Timothy Dalton, Mary Beth Genter, Erik Knudsen, and Ying Xia for their help and encouragement. I would like to extend a special thanks to the classmates and lab partners who have helped me in countless ways over the years. Thank you to Xiaoqing Chang for both her friendship and willingness to help in any way I ever asked of her. From cell maintenance to western blots, from coimmunoprecipitations to PCR reactions, Xiaoqing was always there when I needed her. Thanks to Michael Schnekenberger for his tireless assistance and valuable scientific insight. Thank you as well to Mingya Huang, I have missed your companionship dearly since you left the lab, but have not forgotten your kind and generous spirit. I would also like to acknowledge the many terrific friends I have made through the years, those who have been there to commiserate with me on everything from the hardships of graduate school, relationships and family, to the drudgery of lab retreat planning. I am especially grateful for the support of Chris Curran, Scott Schneider, and Li Peng, always there when I needed to complain. I would like to acknowledge the contribution of all of the faculty members and students in the Department of Environmental Health’s Division of Toxicology. I feel I have received excellent training in this stimulating and critical environment, and I will undoubtedly use the skills I have learned here in many new and exciting ways. Thank you to my friends and family, past and present, for your invaluable perspective and support through this most trying of times. You have truly kept me from going off the deep end. Thanks to the many collaborators for providing various reagents. Their contribution is acknowledged within each chapter. Thanks to grant numbers 2R01 ES06273 and P30 ES06096 of the National Institutes of Environmental Health Sciences (NIEHS) for providing the funding for this research. Also thanks to the University of Cincinnati for support during my first two years of graduate school as a predoctoral Functional Genomics Fellow, and to The Ryan Foundation as well for fellowship support during my last years as a student. vi Table of Contents List of Tables…………………………………………………………………………………... 10 List of Figures………………………………………………………………………………….. 11 Abbreviations…………………………………………………………………………………... 13 Chapter I Introduction…………………………………………………………………………………….. 16 AHR Ligands, Exposure, and Human Health………………………………………………….. 17 TCDD and the AHR……………………………………………………………………………. 21 Physiological Roles of the AHR……………………………………………………………….. 23 The AHR Signaling Pathway…………………………………………………………………... 25 Expanding Roles for the AHR in Gene Expression and the Cell Cycle……………………….. 30 Chapter II Aryl Hydrocarbon Receptor: Cell Cycle Regulation, Toxicity and Tumorigenesis Introduction…………………………………………………………………………………….. 34 AHR ligand-dependent activation of signal transduction pathways…………………………… 35 AHR agonists activate immediate-early response genes………………………………………. 38 Ligand-independent cell cycle control through the AHR……………………………………… 39 AHR-mediated inhibition of apoptosis………………………………………………………… 40 Cell cycle arrest induced by AHR ligands……………………………………………………... 42 Conclusions…………………………………………………………………………………….. 45 References……………………………………………………………………………………… 48 7 Chapter III The Aryl Hydrocarbon Receptor Displaces p300 from E2F-Dependent Promoters and Represses S-Phase Specific Gene Expression Introduction…………………………………………………………………………………….. 61 Materials and Methods…………………………………………………………………………. 64 Results………………………………………………………………………………………….. 71 Discussion……………………………………………………………………………………… 80 References……………………………………………………………………………………… 85 Chapter IV Modulation of E2F-dependent gene expression by an interaction between the AHR and E2F proteins Introduction……………………………………………………………………………………. 105 Materials and Methods………………………………………………………………………… 108 Results…………………………………………………………………………………………. 118 Discussion……………………………………………………………………………………... 129 References……………………………………………………………………………………... 135 Chapter V ChIP-on-chip microarray analysis of AHR promoter binding sites in Hepa-1c1c7 cells Introduction……………………………………………………………………………………. 157 Materials and Methods………………………………………………………………………... 160 Results………………………………………………………………………………………… 164 Discussion……………………………………………………………………………………... 168 References……………………………………………………………………………………... 172 8 Chapter VI Conclusion…………………………………………………………………………………...... 192 References for Introduction and Discussion Sections………………………………………… 200 Appendix……………………………………………………………………………………… 212 9 List of Tables Chapter III Table 1 Gene-specific primer sets for real-time PCR analysis of relative mRNA expression levels……………………………………………………………….. 92 Table 2 Promoter-specific primer sets for chromatin immunoprecipitation analysis…... 92 Chapter IV Table 1 Gene-specific primer sets for real-time PCR analysis of relative
Load more

Recommended publications
  • Supplementary Table S1. Upregulated Genes Differentially
    Supplementary Table S1. Upregulated genes differentially expressed in athletes (p < 0.05 and 1.3-fold change) Gene Symbol p Value Fold Change 221051_s_at NMRK2 0.01 2.38 236518_at CCDC183 0.00 2.05 218804_at ANO1 0.00 2.05 234675_x_at 0.01 2.02 207076_s_at ASS1 0.00 1.85 209135_at ASPH 0.02 1.81 228434_at BTNL9 0.03 1.81 229985_at BTNL9 0.01 1.79 215795_at MYH7B 0.01 1.78 217979_at TSPAN13 0.01 1.77 230992_at BTNL9 0.01 1.75 226884_at LRRN1 0.03 1.74 220039_s_at CDKAL1 0.01 1.73 236520_at 0.02 1.72 219895_at TMEM255A 0.04 1.72 201030_x_at LDHB 0.00 1.69 233824_at 0.00 1.69 232257_s_at 0.05 1.67 236359_at SCN4B 0.04 1.64 242868_at 0.00 1.63 1557286_at 0.01 1.63 202780_at OXCT1 0.01 1.63 1556542_a_at 0.04 1.63 209992_at PFKFB2 0.04 1.63 205247_at NOTCH4 0.01 1.62 1554182_at TRIM73///TRIM74 0.00 1.61 232892_at MIR1-1HG 0.02 1.61 204726_at CDH13 0.01 1.6 1561167_at 0.01 1.6 1565821_at 0.01 1.6 210169_at SEC14L5 0.01 1.6 236963_at 0.02 1.6 1552880_at SEC16B 0.02 1.6 235228_at CCDC85A 0.02 1.6 1568623_a_at SLC35E4 0.00 1.59 204844_at ENPEP 0.00 1.59 1552256_a_at SCARB1 0.02 1.59 1557283_a_at ZNF519 0.02 1.59 1557293_at LINC00969 0.03 1.59 231644_at 0.01 1.58 228115_at GAREM1 0.01 1.58 223687_s_at LY6K 0.02 1.58 231779_at IRAK2 0.03 1.58 243332_at LOC105379610 0.04 1.58 232118_at 0.01 1.57 203423_at RBP1 0.02 1.57 AMY1A///AMY1B///AMY1C///AMY2A///AMY2B// 208498_s_at 0.03 1.57 /AMYP1 237154_at LOC101930114 0.00 1.56 1559691_at 0.01 1.56 243481_at RHOJ 0.03 1.56 238834_at MYLK3 0.01 1.55 213438_at NFASC 0.02 1.55 242290_at TACC1 0.04 1.55 ANKRD20A1///ANKRD20A12P///ANKRD20A2///
    [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]
  • The Myc Target Gene JPO1/CDCA7 Is Frequently Overexpressed in Human Tumors and Has Limited Transforming Activity in Vivo
    Research Article The Myc Target Gene JPO1/CDCA7 Is Frequently Overexpressed in Human Tumors and Has Limited Transforming Activity In vivo Rebecca C. Osthus,1,2 Baktiar Karim,5 Julia E. Prescott,1 B. Douglas Smith,6 Michael McDevitt,2,6 David L. Huso,5 and Chi V. Dang1,2,3,4,6 1Program in Human Genetics and Molecular Biology, 2Division of Hematology, 3Departments of Medicine, Cell Biology, 4Pathology, and 5Comparative Medicine, 6The Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland Abstract metabolism, ribosome biogenesis as well as other cellular processes, how deregulated MYC expression contributes to MYC is frequently overexpressed in human cancers, but the downstream events contributing to tumorigenesis remain tumorigenesis through targets genes remains poorly understood. incompletely understood. MYC encodes an oncogenic tran- In particular, the contributions of large numbers of target genes scription factor, of which target genes presumably contribute with unknown functions to Myc-mediated tumorigenesis remain to cellular transformation. Although Myc regulates about 15% undelineated. Here, we sought to determine the expression pattern of genes and combinations of target genes are likely required of JPO1/CDCA7, which encodes a nuclear protein with unknown for tumorigenesis, we studied in depth the expression of the function, in human cancers and its transforming activity in Myc target gene, JPO1/CDCA7, in human cancers and its ability transgenic mice. to provoke tumorigenesis in transgenic mice. JPO1/CDCA7 is We identified JPO1 as a novel transcript that is differentially regulated in Myc-transformed fibroblasts in a representational frequently overexpressed in human cancers, and in particular, difference analysis screen (13).
    [Show full text]
  • Supplementary Data
    SUPPLEMENTARY DATA A cyclin D1-dependent transcriptional program predicts clinical outcome in mantle cell lymphoma Santiago Demajo et al. 1 SUPPLEMENTARY DATA INDEX Supplementary Methods p. 3 Supplementary References p. 8 Supplementary Tables (S1 to S5) p. 9 Supplementary Figures (S1 to S15) p. 17 2 SUPPLEMENTARY METHODS Western blot, immunoprecipitation, and qRT-PCR Western blot (WB) analysis was performed as previously described (1), using cyclin D1 (Santa Cruz Biotechnology, sc-753, RRID:AB_2070433) and tubulin (Sigma-Aldrich, T5168, RRID:AB_477579) antibodies. Co-immunoprecipitation assays were performed as described before (2), using cyclin D1 antibody (Santa Cruz Biotechnology, sc-8396, RRID:AB_627344) or control IgG (Santa Cruz Biotechnology, sc-2025, RRID:AB_737182) followed by protein G- magnetic beads (Invitrogen) incubation and elution with Glycine 100mM pH=2.5. Co-IP experiments were performed within five weeks after cell thawing. Cyclin D1 (Santa Cruz Biotechnology, sc-753), E2F4 (Bethyl, A302-134A, RRID:AB_1720353), FOXM1 (Santa Cruz Biotechnology, sc-502, RRID:AB_631523), and CBP (Santa Cruz Biotechnology, sc-7300, RRID:AB_626817) antibodies were used for WB detection. In figure 1A and supplementary figure S2A, the same blot was probed with cyclin D1 and tubulin antibodies by cutting the membrane. In figure 2H, cyclin D1 and CBP blots correspond to the same membrane while E2F4 and FOXM1 blots correspond to an independent membrane. Image acquisition was performed with ImageQuant LAS 4000 mini (GE Healthcare). Image processing and quantification were performed with Multi Gauge software (Fujifilm). For qRT-PCR analysis, cDNA was generated from 1 µg RNA with qScript cDNA Synthesis kit (Quantabio). qRT–PCR reaction was performed using SYBR green (Roche).
    [Show full text]
  • UNIVERSITY of CALIFORNIA RIVERSIDE Investigations Into The
    UNIVERSITY OF CALIFORNIA RIVERSIDE Investigations into the Role of TAF1-mediated Phosphorylation in Gene Regulation A Dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in Cell, Molecular and Developmental Biology by Brian James Gadd December 2012 Dissertation Committee: Dr. Xuan Liu, Chairperson Dr. Frank Sauer Dr. Frances M. Sladek Copyright by Brian James Gadd 2012 The Dissertation of Brian James Gadd is approved Committee Chairperson University of California, Riverside Acknowledgments I am thankful to Dr. Liu for her patience and support over the last eight years. I am deeply indebted to my committee members, Dr. Frank Sauer and Dr. Frances Sladek for the insightful comments on my research and this dissertation. Thanks goes out to CMDB, especially Dr. Bachant, Dr. Springer and Kathy Redd for their support. Thanks to all the members of the Liu lab both past and present. A very special thanks to the members of the Sauer lab, including Silvia, Stephane, David, Matt, Stephen, Ninuo, Toby, Josh, Alice, Alex and Flora. You have made all the years here fly by and made them so enjoyable. From the Sladek lab I want to thank Eugene, John, Linh and Karthi. Special thanks go out to all the friends I’ve made over the years here. Chris, Amber, Stephane and David, thank you so much for feeding me, encouraging me and keeping me sane. Thanks to the brothers for all your encouragement and prayers. To any I haven’t mentioned by name, I promise I haven’t forgotten all you’ve done for me during my graduate years.
    [Show full text]
  • Cldn19 Clic2 Clmp Cln3
    NewbornDx™ Advanced Sequencing Evaluation When time to diagnosis matters, the NewbornDx™ Advanced Sequencing Evaluation from Athena Diagnostics delivers rapid, 5- to 7-day results on a targeted 1,722-genes. A2ML1 ALAD ATM CAV1 CLDN19 CTNS DOCK7 ETFB FOXC2 GLUL HOXC13 JAK3 AAAS ALAS2 ATP1A2 CBL CLIC2 CTRC DOCK8 ETFDH FOXE1 GLYCTK HOXD13 JUP AARS2 ALDH18A1 ATP1A3 CBS CLMP CTSA DOK7 ETHE1 FOXE3 GM2A HPD KANK1 AASS ALDH1A2 ATP2B3 CC2D2A CLN3 CTSD DOLK EVC FOXF1 GMPPA HPGD K ANSL1 ABAT ALDH3A2 ATP5A1 CCDC103 CLN5 CTSK DPAGT1 EVC2 FOXG1 GMPPB HPRT1 KAT6B ABCA12 ALDH4A1 ATP5E CCDC114 CLN6 CUBN DPM1 EXOC4 FOXH1 GNA11 HPSE2 KCNA2 ABCA3 ALDH5A1 ATP6AP2 CCDC151 CLN8 CUL4B DPM2 EXOSC3 FOXI1 GNAI3 HRAS KCNB1 ABCA4 ALDH7A1 ATP6V0A2 CCDC22 CLP1 CUL7 DPM3 EXPH5 FOXL2 GNAO1 HSD17B10 KCND2 ABCB11 ALDOA ATP6V1B1 CCDC39 CLPB CXCR4 DPP6 EYA1 FOXP1 GNAS HSD17B4 KCNE1 ABCB4 ALDOB ATP7A CCDC40 CLPP CYB5R3 DPYD EZH2 FOXP2 GNE HSD3B2 KCNE2 ABCB6 ALG1 ATP8A2 CCDC65 CNNM2 CYC1 DPYS F10 FOXP3 GNMT HSD3B7 KCNH2 ABCB7 ALG11 ATP8B1 CCDC78 CNTN1 CYP11B1 DRC1 F11 FOXRED1 GNPAT HSPD1 KCNH5 ABCC2 ALG12 ATPAF2 CCDC8 CNTNAP1 CYP11B2 DSC2 F13A1 FRAS1 GNPTAB HSPG2 KCNJ10 ABCC8 ALG13 ATR CCDC88C CNTNAP2 CYP17A1 DSG1 F13B FREM1 GNPTG HUWE1 KCNJ11 ABCC9 ALG14 ATRX CCND2 COA5 CYP1B1 DSP F2 FREM2 GNS HYDIN KCNJ13 ABCD3 ALG2 AUH CCNO COG1 CYP24A1 DST F5 FRMD7 GORAB HYLS1 KCNJ2 ABCD4 ALG3 B3GALNT2 CCS COG4 CYP26C1 DSTYK F7 FTCD GP1BA IBA57 KCNJ5 ABHD5 ALG6 B3GAT3 CCT5 COG5 CYP27A1 DTNA F8 FTO GP1BB ICK KCNJ8 ACAD8 ALG8 B3GLCT CD151 COG6 CYP27B1 DUOX2 F9 FUCA1 GP6 ICOS KCNK3 ACAD9 ALG9
    [Show full text]
  • This Thesis Has Been Submitted in Fulfilment of the Requirements for a Postgraduate Degree (E.G
    This thesis has been submitted in fulfilment of the requirements for a postgraduate degree (e.g. PhD, MPhil, DClinPsychol) at the University of Edinburgh. Please note the following terms and conditions of use: This work is protected by copyright and other intellectual property rights, which are retained by the thesis author, unless otherwise stated. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the author. The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the author. When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given. Investigation into the role of LSH ATPase in chromatin remodelling Alina Gukova Doctor of Philosophy – University of Edinburgh – 2020 ABSTRACT Chromatin remodelling is a crucial nuclear process affecting replication, transcription and repair. Global reduction of DNA methylation is observed in Immunodeficiency-Centromeric Instability-Facial Anomaly (ICF) syndrome. Several proteins were found to be mutated in patients diagnosed with ICF, among them are LSH and CDCA7. LSH is a chromatin remodeller bearing homology to the members of Sf2 remodelling family. A point mutation in its ATPase lobe was identified in ICF. CDCA7 is a zinc finger protein that was recently found to be crucial for nucleosome remodelling activity of LSH. Several point mutations in its zinc finger domain were described in ICF patients. In vitro and in vivo studies have shown that LSH-/- phenotype demonstrates reduction of global DNA methylation, implying that chromatin remodelling LSH functions may be required for the efficient methyltransferase activity, linking this finding to ICF phenotype.
    [Show full text]
  • 1 No. Affymetrix ID Gene Symbol Genedescription Gotermsbp Q Value 1. 209351 at KRT14 Keratin 14 Structural Constituent of Cyto
    1 Affymetrix Gene Q No. GeneDescription GOTermsBP ID Symbol value structural constituent of cytoskeleton, intermediate 1. 209351_at KRT14 keratin 14 filament, epidermis development <0.01 biological process unknown, S100 calcium binding calcium ion binding, cellular 2. 204268_at S100A2 protein A2 component unknown <0.01 regulation of progression through cell cycle, extracellular space, cytoplasm, cell proliferation, protein kinase C inhibitor activity, protein domain specific 3. 33323_r_at SFN stratifin/14-3-3σ binding <0.01 regulation of progression through cell cycle, extracellular space, cytoplasm, cell proliferation, protein kinase C inhibitor activity, protein domain specific 4. 33322_i_at SFN stratifin/14-3-3σ binding <0.01 structural constituent of cytoskeleton, intermediate 5. 201820_at KRT5 keratin 5 filament, epidermis development <0.01 structural constituent of cytoskeleton, intermediate 6. 209125_at KRT6A keratin 6A filament, ectoderm development <0.01 regulation of progression through cell cycle, extracellular space, cytoplasm, cell proliferation, protein kinase C inhibitor activity, protein domain specific 7. 209260_at SFN stratifin/14-3-3σ binding <0.01 structural constituent of cytoskeleton, intermediate 8. 213680_at KRT6B keratin 6B filament, ectoderm development <0.01 receptor activity, cytosol, integral to plasma membrane, cell surface receptor linked signal transduction, sensory perception, tumor-associated calcium visual perception, cell 9. 202286_s_at TACSTD2 signal transducer 2 proliferation, membrane <0.01 structural constituent of cytoskeleton, cytoskeleton, intermediate filament, cell-cell adherens junction, epidermis 10. 200606_at DSP desmoplakin development <0.01 lectin, galactoside- sugar binding, extracellular binding, soluble, 7 space, nucleus, apoptosis, 11. 206400_at LGALS7 (galectin 7) heterophilic cell adhesion <0.01 2 S100 calcium binding calcium ion binding, epidermis 12. 205916_at S100A7 protein A7 (psoriasin 1) development <0.01 S100 calcium binding protein A8 (calgranulin calcium ion binding, extracellular 13.
    [Show full text]
  • A Set of Regulatory Genes Co-Expressed in Embryonic Human Brain Is Implicated in Disrupted Speech Development
    Molecular Psychiatry https://doi.org/10.1038/s41380-018-0020-x ARTICLE A set of regulatory genes co-expressed in embryonic human brain is implicated in disrupted speech development 1 1 1 2 3 Else Eising ● Amaia Carrion-Castillo ● Arianna Vino ● Edythe A. Strand ● Kathy J. Jakielski ● 4,5 6 7 8 9 Thomas S. Scerri ● Michael S. Hildebrand ● Richard Webster ● Alan Ma ● Bernard Mazoyer ● 1,10 4,5 6,11 6,12 13 Clyde Francks ● Melanie Bahlo ● Ingrid E. Scheffer ● Angela T. Morgan ● Lawrence D. Shriberg ● Simon E. Fisher 1,10 Received: 22 September 2017 / Revised: 3 December 2017 / Accepted: 2 January 2018 © The Author(s) 2018. This article is published with open access Abstract Genetic investigations of people with impaired development of spoken language provide windows into key aspects of human biology. Over 15 years after FOXP2 was identified, most speech and language impairments remain unexplained at the molecular level. We sequenced whole genomes of nineteen unrelated individuals diagnosed with childhood apraxia of speech, a rare disorder enriched for causative mutations of large effect. Where DNA was available from unaffected parents, CHD3 SETD1A WDR5 fi 1234567890();,: we discovered de novo mutations, implicating genes, including , and . In other probands, we identi ed novel loss-of-function variants affecting KAT6A, SETBP1, ZFHX4, TNRC6B and MKL2, regulatory genes with links to neurodevelopment. Several of the new candidates interact with each other or with known speech-related genes. Moreover, they show significant clustering within a single co-expression module of genes highly expressed during early human brain development. This study highlights gene regulatory pathways in the developing brain that may contribute to acquisition of proficient speech.
    [Show full text]
  • Structural Basis of Specific DNA Binding by the Transcription Factor
    8388–8398 Nucleic Acids Research, 2019, Vol. 47, No. 16 Published online 21 June 2019 doi: 10.1093/nar/gkz557 Structural basis of specific DNA binding by the transcription factor ZBTB24 Ren Ren1,†, Swanand Hardikar1,†, John R. Horton1, Yue Lu1, Yang Zeng1,2,AnupK.Singh1, Kevin Lin1, Luis Della Coletta1, Jianjun Shen1,2, Celine Shuet Lin Kong3, Hideharu Hashimoto4, Xing Zhang1, Taiping Chen1,2,* and Xiaodong Cheng 1,2,* 1Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, 2 Houston, TX 77030, USA, Program in Genetics and Epigenetics, The University of Texas MD Anderson Cancer Downloaded from https://academic.oup.com/nar/article/47/16/8388/5521786 by guest on 23 September 2021 Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA, 3Program in Cancer Biology, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA and 4Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA Received October 13, 2018; Revised June 07, 2019; Editorial Decision June 11, 2019; Accepted June 13, 2019 ABSTRACT INTRODUCTION ZBTB24, encoding a protein of the ZBTB family ZBTB (zinc-finger- and BTB domain-containing) proteins, of transcriptional regulators, is one of four known characterized by the presence of an N-terminal BTB genes––the other three being DNMT3B, CDCA7 and (broad-complex, tram-track, and bric-a-brac)` domain [also HELLS––that are mutated in immunodeficiency, cen- known as POZ (poxvirus and zinc finger) domain] and a tromeric instability and facial anomalies (ICF) syn- C-terminal domain with tandem C2H2 Kr¨uppel-type zinc fingers (ZFs), are a large family of evolutionarily con- drome, a genetic disorder characterized by DNA hy- served transcriptional regulators (1).
    [Show full text]
  • Dynein Activators and Adaptors at a Glance Mara A
    © 2019. Published by The Company of Biologists Ltd | Journal of Cell Science (2019) 132, jcs227132. doi:10.1242/jcs.227132 CELL SCIENCE AT A GLANCE Dynein activators and adaptors at a glance Mara A. Olenick and Erika L. F. Holzbaur* ABSTRACT ribonucleoprotein particles for BICD2, and signaling endosomes for Cytoplasmic dynein-1 (hereafter dynein) is an essential cellular motor Hook1. In this Cell Science at a Glance article and accompanying that drives the movement of diverse cargos along the microtubule poster, we highlight the conserved structural features found in dynein cytoskeleton, including organelles, vesicles and RNAs. A long- activators, the effects of these activators on biophysical parameters, standing question is how a single form of dynein can be adapted to a such as motor velocity and stall force, and the specific intracellular wide range of cellular functions in both interphase and mitosis. functions they mediate. – Recent progress has provided new insights dynein interacts with a KEY WORDS: BICD2, Cytoplasmic dynein, Dynactin, Hook1, group of activating adaptors that provide cargo-specific and/or Microtubule motors, Trafficking function-specific regulation of the motor complex. Activating adaptors such as BICD2 and Hook1 enhance the stability of the Introduction complex that dynein forms with its required activator dynactin, leading Microtubule-based transport is vital to cellular development and to highly processive motility toward the microtubule minus end. survival. Microtubules provide a polarized highway to facilitate Furthermore, activating adaptors mediate specific interactions of the active transport by the molecular motors dynein and kinesin. While motor complex with cargos such as Rab6-positive vesicles or many types of kinesins drive transport toward microtubule plus- ends, there is only one major form of dynein, cytoplasmic dynein-1, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, which drives the trafficking of a wide array of minus-end-directed USA.
    [Show full text]
  • Transcriptome Analysis of Sézary Syndrome and Lymphocytic- Variant Hypereosinophilic Syndrome T Cells Reveals Common and Divergent Genes
    www.oncotarget.com Oncotarget, 2019, Vol. 10, (No. 49), pp: 5052-5069 Research Paper Transcriptome analysis of Sézary syndrome and lymphocytic- variant hypereosinophilic syndrome T cells reveals common and divergent genes Andrea M. Moerman-Herzog1, Daniel A. Acheampong1,2, Amanda G. Brooks1, Suzan M. Blair1, Ping-Ching Hsu3 and Henry K. Wong1 1Department of Dermatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA 2Joint Graduate Program in Bioinformatics, University of Arkansas at Little Rock and University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA 3Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA Correspondence to: Henry K. Wong, email: [email protected] Keywords: Sézary syndrome; lymphocytic-variant hypereosinophilic syndrome; biomarkers; microarrays; progression Received: May 24, 2019 Accepted: July 15, 2019 Published: August 20, 2019 Copyright: Moerman-Herzog et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Sézary syndrome (SS) is an aggressive cutaneous T cell lymphoma with pruritic skin inflammation and immune dysfunction, driven by neoplastic, clonal memory T cells in both peripheral blood and skin. To gain insight into abnormal gene expression promoting T cell dysfunction, lymphoproliferation and transformation in SS, we first compared functional transcriptomic profiles of both resting and activated CD4+CD45RO+ T cells from SS patients and normal donors to identified differential expressed genes. Next, a meta-analysis was performed to compare our SS data to public microarray data from a novel benign disease control, lymphocytic-variant hypereosinophilic syndrome (L-HES).
    [Show full text]