Upon Microbial Challenge, Human Neutrophils Undergo Rapid Changes in Nuclear Architecture and Chromatin Folding to Orchestrate an Immediate Inflammatory Gene Program
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Revealing the Mechanism of Xist-Mediated Silencing
Revealing the Mechanism of Xist-mediated Silencing Thesis by Chun-Kan Chen In Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy CALIFORNIA INSTITUTE OF TECHNOLOGY Pasadena, California 2018 Defended November 1, 2017 ii 2017 Chun-Kan Chen ORCID: 0000-0002-1194-9137 iii ACKNOWLEDGEMENTS First of all, I’d like to thank my great mentor, Dr. Mitch Guttman (California Institute of Technology, Pasadena, CA), who led me to become an independent researcher and gave me valuable advice that guided me to accomplish this thesis. He has always been supportive of my future plans and career goals. I really enjoyed every discussion we have had. We often generated some interesting ideas for projects during our discussions. I would also like to send my thanks to my lab mates, Amy Chow, Mario Blanco, and Erik Aznauryan, who helped me with many experiments to move the project forward. I’d like to acknowledge Dr. Kathrin Plath (University of California, Los Angeles, Los Angeles, CA) for the collaboration and his critical comments on this project. Also, I want to thank Jesse Engreitz and Patrick McDonel, who provided helpful comments and suggestions to the project. I want to thank my parents, brother, and parents-in-law who provided both instrumental and emotional support to assist me in completing my Ph.D. degree. I also want to thank my friends, Lily Chen, Pei-Ying Lin, Tzu-Yao Wang, and Wei Li, for giving me valuable social support during my years in graduate school. Last but not least, I would like to send my special thanks to my wife, Christine Juang, who has always been supportive. -
The Mutational Landscape of Myeloid Leukaemia in Down Syndrome
cancers Review The Mutational Landscape of Myeloid Leukaemia in Down Syndrome Carini Picardi Morais de Castro 1, Maria Cadefau 1,2 and Sergi Cuartero 1,2,* 1 Josep Carreras Leukaemia Research Institute (IJC), Campus Can Ruti, 08916 Badalona, Spain; [email protected] (C.P.M.d.C); [email protected] (M.C.) 2 Germans Trias i Pujol Research Institute (IGTP), Campus Can Ruti, 08916 Badalona, Spain * Correspondence: [email protected] Simple Summary: Leukaemia occurs when specific mutations promote aberrant transcriptional and proliferation programs, which drive uncontrolled cell division and inhibit the cell’s capacity to differentiate. In this review, we summarize the most frequent genetic lesions found in myeloid leukaemia of Down syndrome, a rare paediatric leukaemia specific to individuals with trisomy 21. The evolution of this disease follows a well-defined sequence of events and represents a unique model to understand how the ordered acquisition of mutations drives malignancy. Abstract: Children with Down syndrome (DS) are particularly prone to haematopoietic disorders. Paediatric myeloid malignancies in DS occur at an unusually high frequency and generally follow a well-defined stepwise clinical evolution. First, the acquisition of mutations in the GATA1 transcription factor gives rise to a transient myeloproliferative disorder (TMD) in DS newborns. While this condition spontaneously resolves in most cases, some clones can acquire additional mutations, which trigger myeloid leukaemia of Down syndrome (ML-DS). These secondary mutations are predominantly found in chromatin and epigenetic regulators—such as cohesin, CTCF or EZH2—and Citation: de Castro, C.P.M.; Cadefau, in signalling mediators of the JAK/STAT and RAS pathways. -
Nuclear Domains
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Cold Spring Harbor Laboratory Institutional Repository CELL SCIENCE AT A GLANCE 2891 Nuclear domains dynamic structures and, in addition, nuclear pore complex has been shown to rapid protein exchange occurs between have a remarkable substructure, in which David L. Spector many of the domains and the a basket extends into the nucleoplasm. Cold Spring Harbor Laboratory, One Bungtown nucleoplasm (Misteli, 2001). An The peripheral nuclear lamina lies Road, Cold Spring Harbor, NY 11724, USA extensive effort is currently underway by inside the nuclear envelope and is (e-mail: [email protected]) numerous laboratories to determine the composed of lamins A/C and B and is biological function(s) associated with thought to play a role in regulating Journal of Cell Science 114, 2891-2893 (2001) © The Company of Biologists Ltd each domain. The accompanying poster nuclear envelope structure and presents an overview of commonly anchoring interphase chromatin at the The mammalian cell nucleus is a observed nuclear domains. nuclear periphery. Internal patches of membrane-bound organelle that contains lamin protein are also present in the the machinery essential for gene The nucleus is bounded by a nuclear nucleoplasm (Moir et al., 2000). The expression. Although early studies envelope, a double-membrane structure, cartoon depicts much of the nuclear suggested that little organization exists of which the outer membrane is envelope/peripheral lamina as within this compartment, more contiguous with the rough endoplasmic transparent, so that internal structures contemporary studies have identified an reticulum and is often studded with can be more easily observed. -
Structure of the Human Cohesin Inhibitor Wapl
Structure of the human cohesin inhibitor Wapl Zhuqing Ouyanga,1, Ge Zhenga,1, Jianhua Songb, Dominika M. Borekc, Zbyszek Otwinowskic, Chad A. Brautigamc, Diana R. Tomchickc, Susannah Rankinb, and Hongtao Yua,2 aHoward Hughes Medical Institute, Department of Pharmacology, and cDepartment of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390; and bProgram in Cell Cycle and Cancer Biology, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104 Edited by Douglas Koshland, University of California, Berkeley, CA, and approved May 23, 2013 (received for review March 11, 2013) Cohesin, along with positive regulators, establishes sister-chromatid trigger cohesin release from chromosome arms (15, 18–21). A pool of cohesion by forming a ring to circle chromatin. The wings apart-like cohesin at centromeres is protected by the shugoshin (Sgo1)–protein protein (Wapl) is a key negative regulator of cohesin and forms phosphatase 2A (PP2A) complex (22, 23), which binds to cohesin, a complex with precocious dissociation of sisters protein 5 (Pds5) to dephosphorylates sororin, and protects cohesin from Wapl promote cohesin release from chromatin. Here we report the at centromeres (24). After all sister kinetochores attach properly crystal structure and functional characterization of human Wapl. to the mitotic spindle and are under tension, separase cleaves Wapl contains a flexible, variable N-terminal region (Wapl-N) and centromeric cohesin to initiate sister-chromatid separation. The a conserved C-terminal domain (Wapl-C) consisting of eight HEAT separated chromatids are evenly partitioned into the two daughter (Huntingtin, Elongation factor 3, A subunit, and target of rapamycin) cells through their attachment to microtubules originating from the repeats. -
Ultrasound-Assisted Nonviral Gene Transfer of AQP1 to the Irradiated Minipig Parotid Gland Restores fluid Secretion
Gene Therapy (2015) 22, 739–749 © 2015 Macmillan Publishers Limited All rights reserved 0969-7128/15 www.nature.com/gt ORIGINAL ARTICLE Ultrasound-assisted nonviral gene transfer of AQP1 to the irradiated minipig parotid gland restores fluid secretion Z Wang1, L Zourelias1,CWu1, PC Edwards2, M Trombetta3 and MJ Passineau1 Xerostomia is a common side effect of ionizing radiation used to treat head and neck cancer. A groundbreaking Phase I human clinical trial using Adenoviral gene transfer of Aquaporin-1 (AQP1) to a single salivary gland of individuals suffering from radiation- induced xerostomia has recently been reported. Unfortunately, the limitations of the Adenoviral vector system used in this pioneering trial preclude its advancement to a Phase II trial, and we have thus undertaken to evaluate the therapeutic potential of ultrasound-assisted nonviral gene transfer (UAGT) as an alternative means of delivering AQP1 gene therapy to the salivary gland by comparing head-to-head with the canonical Adenoviral vector in a swine model. Swine irradiated unilaterally with a 10-Gy electron beam targeted at the parotid gland suffered from significant, sustained hyposalivation that was bilateral, despite irradiation being confined to the targeted gland. Unilateral AQP1 gene therapy with UAGT resulted in bilateral restoration of stimulated salivary flow at 48 h and 1 week post treatment (1.62 ± 0.48 ml and 1.87 ± 0.45 ml) to preinjury levels (1.34 ± 0.14 ml) in a manner comparable to Adenoviral delivery (2.32 ± 0.6 ml and 1.33 ± 0.97 ml). UAGT can replace the Adenoviral vector as a means of delivering AQP1 gene therapy in the irradiated swine model, and it is a candidate for advancement to a Phase I human clinical trial. -
A Requirement for STAG2 in Replication Fork Progression Creates a Targetable Synthetic Lethality in Cohesin-Mutant Cancers
ARTICLE https://doi.org/10.1038/s41467-019-09659-z OPEN A requirement for STAG2 in replication fork progression creates a targetable synthetic lethality in cohesin-mutant cancers Gourish Mondal1, Meredith Stevers1, Benjamin Goode 1, Alan Ashworth2,3 & David A. Solomon 1,2 Cohesin is a multiprotein ring that is responsible for cohesion of sister chromatids and formation of DNA loops to regulate gene expression. Genomic analyses have identified that 1234567890():,; the cohesin subunit STAG2 is frequently inactivated by mutations in cancer. However, the reason STAG2 mutations are selected during tumorigenesis and strategies for therapeutically targeting mutant cancer cells are largely unknown. Here we show that STAG2 is essential for DNA replication fork progression, whereby STAG2 inactivation in non-transformed cells leads to replication fork stalling and collapse with disruption of interaction between the cohesin ring and the replication machinery as well as failure to establish SMC3 acetylation. As a con- sequence, STAG2 mutation confers synthetic lethality with DNA double-strand break repair genes and increased sensitivity to select cytotoxic chemotherapeutic agents and PARP or ATR inhibitors. These studies identify a critical role for STAG2 in replication fork procession and elucidate a potential therapeutic strategy for cohesin-mutant cancers. 1 Department of Pathology, University of California, San Francisco, CA 94143, USA. 2 UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA. 3 Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, CA 94158, USA. Correspondence and requests for materials should be addressed to D.A.S. (email: [email protected]) NATURE COMMUNICATIONS | (2019) 10:1686 | https://doi.org/10.1038/s41467-019-09659-z | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-09659-z ohesin is a multi-protein complex composed of four core transcriptional dysregulation22,23. -
Nuclear Envelope Laminopathies: Evidence for Developmentally Inappropriate Nuclear Envelope-Chromatin Associations
Nuclear Envelope Laminopathies: Evidence for Developmentally Inappropriate Nuclear Envelope-Chromatin Associations by Jelena Perovanovic M.S. in Molecular Biology and Physiology, September 2009, University of Belgrade M.Phil. in Molecular Medicine, August 2013, The George Washington University A Dissertation submitted to The Faculty of The Columbian College of Arts and Sciences of The George Washington University in partial fulfillment of the requirements for the degree of Doctor of Philosophy August 31, 2015 Dissertation directed by Eric P. Hoffman Professor of Integrative Systems Biology The Columbian College of Arts and Sciences of The George Washington University certifies that Jelena Perovanovic has passed the Final Examination for the degree of Doctor of Philosophy as of May 5, 2015. This is the final and approved form of the dissertation. Nuclear Envelope Laminopathies: Evidence for Developmentally Inappropriate Nuclear Envelope-Chromatin Associations Jelena Perovanovic Dissertation Research Committee: Eric P. Hoffman, Professor of Integrative Systems Biology, Dissertation Director Anamaris Colberg-Poley, Professor of Integrative Systems Biology, Committee Member Robert J. Freishtat, Associate Professor of Pediatrics, Committee Member Vittorio Sartorelli, Senior Investigator, National Institutes of Health, Committee Member ii © Copyright 2015 by Jelena Perovanovic All rights reserved iii Acknowledgments I am deeply indebted to countless individuals for their support and encouragement during the past five years of graduate studies. First and foremost, I would like to express my gratitude to my mentor, Dr. Eric P. Hoffman, for his unwavering support and guidance, and keen attention to my professional development. This Dissertation would not have been possible without the critical input he provided and the engaging environment he created. -
Dynamic Force-Induced Direct Dissociation of Protein Complexes in a Nuclear Body in Living Cells
ARTICLE Received 13 Jan 2012 | Accepted 26 Apr 2012 | Published 29 May 2012 DOI: 10.1038/ncomms1873 Dynamic force-induced direct dissociation of protein complexes in a nuclear body in living cells Yeh-Chuin Poh1, Sergey P. Shevtsov2, Farhan Chowdhury1, Douglas C. Wu1, Sungsoo Na3, Miroslav Dundr2 & Ning Wang1 Despite past progress in understanding mechanisms of cellular mechanotransduction, it is unclear whether a local surface force can directly alter nuclear functions without intermediate biochemical cascades. Here we show that a local dynamic force via integrins results in direct displacements of coilin and SMN proteins in Cajal bodies and direct dissociation of coilin-SMN associated complexes. Spontaneous movements of coilin increase more than those of SMN in the same Cajal body after dynamic force application. Fluorescence resonance energy transfer changes of coilin-SMN depend on force magnitude, an intact F-actin, cytoskeletal tension, Lamin A/C, or substrate rigidity. Other protein pairs in Cajal bodies exhibit different magnitudes of fluorescence resonance energy transfer. Dynamic cyclic force induces tiny phase lags between various protein pairs in Cajal bodies, suggesting viscoelastic interactions between them. These findings demonstrate that dynamic force-induced direct structural changes of protein complexes in Cajal bodies may represent a unique mechanism of mechanotransduction that impacts on nuclear functions involved in gene expression. 1 Department of Mechanical Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, Champaign, Illinois 61801, USA. 2 Department of Cell Biology, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064, USA. 3 Department of Biomedical Engineering, Indiana University-Purdue University Indianapolis, Indiana 46202, USA. -
Nucleolus: a Central Hub for Nuclear Functions Olga Iarovaia, Elizaveta Minina, Eugene Sheval, Daria Onichtchouk, Svetlana Dokudovskaya, Sergey Razin, Yegor Vassetzky
Nucleolus: A Central Hub for Nuclear Functions Olga Iarovaia, Elizaveta Minina, Eugene Sheval, Daria Onichtchouk, Svetlana Dokudovskaya, Sergey Razin, Yegor Vassetzky To cite this version: Olga Iarovaia, Elizaveta Minina, Eugene Sheval, Daria Onichtchouk, Svetlana Dokudovskaya, et al.. Nucleolus: A Central Hub for Nuclear Functions. Trends in Cell Biology, Elsevier, 2019, 29 (8), pp.647-659. 10.1016/j.tcb.2019.04.003. hal-02322927 HAL Id: hal-02322927 https://hal.archives-ouvertes.fr/hal-02322927 Submitted on 18 Nov 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Nucleolus: A Central Hub for Nuclear Functions Olga Iarovaia, Elizaveta Minina, Eugene Sheval, Daria Onichtchouk, Svetlana Dokudovskaya, Sergey Razin, Yegor Vassetzky To cite this version: Olga Iarovaia, Elizaveta Minina, Eugene Sheval, Daria Onichtchouk, Svetlana Dokudovskaya, et al.. Nucleolus: A Central Hub for Nuclear Functions. Trends in Cell Biology, Elsevier, 2019, 29 (8), pp.647-659. 10.1016/j.tcb.2019.04.003. hal-02322927 HAL Id: hal-02322927 https://hal.archives-ouvertes.fr/hal-02322927 Submitted on 18 Nov 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. -
Lecture9'21 Chromatin II
Genetic Organization -Chromosomal Arrangement: From Form to Function. Chapters 9 & 10 in Genes XI The Eukaryotic chromosome – Organized Structures -banding – Centromeres – Telomeres – Nucleosomes – Euchromatin / Heterochromatin – Higher Orders of Chromosomal Structure 2 Heterochromatin differs from euchromatin in that heterochromatin is effectively inert; remains condensed during interphase; is transcriptionally repressed; replicates late in S phase and may be localized to the centromere or nuclear periphery Facultative heterochromatin is not restricted by pre-designated sequence; genes that are moved within or near heterochromatic regions can become inactivated as a result of their new location. Heterochromatin differs from euchromatin in that heterochromatin is effectively inert; remains condensed during interphase; is transcriptionally repressed; replicates late in S phase and may be localized to the centromere or nuclear periphery Facultative heterochromatin is not restricted by pre-designated sequence; genes that are moved within or near heterochromatic regions can become inactivated as a result of their new location. Chromatin inactivation (or heterochromatin formation) occurs by the addition of proteins to the nucleosomal fiber. May be due to: Chromatin condensation -making it inaccessible to transcriptional apparatus Proteins that accumulate and inhibit accessibility to the regulatory sequences Proteins that directly inhibit transcription Chromatin Is Fundamentally Divided into Euchromatin and Heterochromatin • Individual chromosomes can be seen only during mitosis. • During interphase, the general mass of chromatin is in the form of euchromatin, which is slightly less tightly packed than mitotic chromosomes. TF20210119 Regions of compact heterochromatin are clustered near the nucleolus and nuclear membrane Photo courtesy of Edmund Puvion, Centre National de la Recherche Scientifique Chromatin: Basic Structures • nucleosome – The basic structural subunit of chromatin, consisting of ~200 bp of DNA wrapped around an octamer of histone proteins. -
THE DEVELOPMENT of CHEMICAL METHODS to DISCOVER KINASE SUBSTRATES and MAP CELL SIGNALING with GAMMA-MODIFIED ATP ANALOG-DEPENDENT KINASE-CATALYZED PHOSPHORYLATION By
Wayne State University Wayne State University Dissertations 1-1-2017 The evelopmeD nt Of Chemical Methods To Discover Kinase Substrates And Map Cell Signaling With Gamma-Modified Atp Analog- Dependent Kinase-Catalyzed Phosphorylation Dissanayaka Mudiyanselage Maheeka Madhubashini Embogama Wayne State University, Follow this and additional works at: https://digitalcommons.wayne.edu/oa_dissertations Part of the Analytical Chemistry Commons, and the Biochemistry Commons Recommended Citation Embogama, Dissanayaka Mudiyanselage Maheeka Madhubashini, "The eD velopment Of Chemical Methods To Discover Kinase Substrates And Map Cell Signaling With Gamma-Modified Atp Analog-Dependent Kinase-Catalyzed Phosphorylation" (2017). Wayne State University Dissertations. 1698. https://digitalcommons.wayne.edu/oa_dissertations/1698 This Open Access Dissertation is brought to you for free and open access by DigitalCommons@WayneState. It has been accepted for inclusion in Wayne State University Dissertations by an authorized administrator of DigitalCommons@WayneState. THE DEVELOPMENT OF CHEMICAL METHODS TO DISCOVER KINASE SUBSTRATES AND MAP CELL SIGNALING WITH GAMMA-MODIFIED ATP ANALOG-DEPENDENT KINASE-CATALYZED PHOSPHORYLATION by DISSANAYAKA M. MAHEEKA M. EMBOGAMA DISSERTATION Submitted to the Graduate School of Wayne State University, Detroit, Michigan in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY 2017 MAJOR: CHEMISTRY (Biochemistry) Approved By: Advisor Date DEDICATION To my beloved mother, father, husband, daughter and sister. ii ACKNOWLEGEMENTS Many people have helped me during the past five years of earning my PhD. I would like to take this opportunity to convey my gratitude to them. First and foremost, I would like to thank my research supervisor Dr. Mary Kay Pflum for being the greatest mentor that I have met so far. -
The Emerging Role of Cohesin in the DNA Damage Response
G C A T T A C G G C A T genes Review The Emerging Role of Cohesin in the DNA Damage Response Ireneusz Litwin * , Ewa Pilarczyk and Robert Wysocki Institute of Experimental Biology, University of Wroclaw, 50-328 Wroclaw, Poland; [email protected] (E.P.); [email protected] (R.W.) * Correspondence: [email protected]; Tel.: +48-71-375-4126 Received: 29 October 2018; Accepted: 21 November 2018; Published: 28 November 2018 Abstract: Faithful transmission of genetic material is crucial for all organisms since changes in genetic information may result in genomic instability that causes developmental disorders and cancers. Thus, understanding the mechanisms that preserve genome integrity is of fundamental importance. Cohesin is a multiprotein complex whose canonical function is to hold sister chromatids together from S-phase until the onset of anaphase to ensure the equal division of chromosomes. However, recent research points to a crucial function of cohesin in the DNA damage response (DDR). In this review, we summarize recent advances in the understanding of cohesin function in DNA damage signaling and repair. First, we focus on cohesin architecture and molecular mechanisms that govern sister chromatid cohesion. Next, we briefly characterize the main DDR pathways. Finally, we describe mechanisms that determine cohesin accumulation at DNA damage sites and discuss possible roles of cohesin in DDR. Keywords: cohesin; cohesin loader; DNA double-strand breaks; replication stress; DNA damage tolerance 1. Introduction Genomes of all living organisms are continuously challenged by endogenous and exogenous insults that threaten genome stability. It has been estimated that human cells suffer more than 70,000 DNA lesions per day, most of which are single-strand DNA breaks (SSBs) [1].