An Atlas of Tissue-Specific Conserved Coexpression for Functional
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Exceptional Conservation of Horse–Human Gene Order on X Chromosome Revealed by High-Resolution Radiation Hybrid Mapping
Exceptional conservation of horse–human gene order on X chromosome revealed by high-resolution radiation hybrid mapping Terje Raudsepp*†, Eun-Joon Lee*†, Srinivas R. Kata‡, Candice Brinkmeyer*, James R. Mickelson§, Loren C. Skow*, James E. Womack‡, and Bhanu P. Chowdhary*¶ʈ *Department of Veterinary Anatomy and Public Health, ‡Department of Veterinary Pathobiology, College of Veterinary Medicine, and ¶Department of Animal Science, College of Agriculture and Life Science, Texas A&M University, College Station, TX 77843; and §Department of Veterinary Pathobiology, University of Minnesota, 295f AS͞VM, St. Paul, MN 55108 Contributed by James E. Womack, December 30, 2003 Development of a dense map of the horse genome is key to efforts ciated with the traits, once they are mapped by genetic linkage aimed at identifying genes controlling health, reproduction, and analyses with highly polymorphic markers. performance. We herein report a high-resolution gene map of the The X chromosome is the most conserved mammalian chro- horse (Equus caballus) X chromosome (ECAX) generated by devel- mosome (18, 19). Extensive comparisons of structure, organi- oping and typing 116 gene-specific and 12 short tandem repeat zation, and gene content of this chromosome in evolutionarily -markers on the 5,000-rad horse ؋ hamster whole-genome radia- diverse mammals have revealed a remarkable degree of conser tion hybrid panel and mapping 29 gene loci by fluorescence in situ vation (20–22). Until now, the chromosome has been best hybridization. The human X chromosome sequence was used as a studied in humans and mice, where the focus of research has template to select genes at 1-Mb intervals to develop equine been the intriguing patterns of X inactivation and the involve- orthologs. -
Reframing Psychiatry for Precision Medicine
Reframing Psychiatry for Precision Medicine Elizabeth B Torres 1,2,3* 1 Rutgers University Department of Psychology; [email protected] 2 Rutgers University Center for Cognitive Science (RUCCS) 3 Rutgers University Computer Science, Center for Biomedicine Imaging and Modelling (CBIM) * Correspondence: [email protected]; Tel.: (011) +858-445-8909 (E.B.T) Supplementary Material Sample Psychological criteria that sidelines sensory motor issues in autism: The ADOS-2 manual [1, 2], under the “Guidelines for Selecting a Module” section states (emphasis added): “Note that the ADOS-2 was developed for and standardized using populations of children and adults without significant sensory and motor impairments. Standardized use of any ADOS-2 module presumes that the individual can walk independently and is free of visual or hearing impairments that could potentially interfere with use of the materials or participation in specific tasks.” Sample Psychiatric criteria from the DSM-5 [3] that does not include sensory-motor issues: A. Persistent deficits in social communication and social interaction across multiple contexts, as manifested by the following, currently or by history (examples are illustrative, not exhaustive, see text): 1. Deficits in social-emotional reciprocity, ranging, for example, from abnormal social approach and failure of normal back-and-forth conversation; to reduced sharing of interests, emotions, or affect; to failure to initiate or respond to social interactions. 2. Deficits in nonverbal communicative behaviors used for social interaction, ranging, for example, from poorly integrated verbal and nonverbal communication; to abnormalities in eye contact and body language or deficits in understanding and use of gestures; to a total lack of facial expressions and nonverbal communication. -
Escape from X Chromosome Inactivation Is an Intrinsic Property of the Jarid1c Locus
Escape from X chromosome inactivation is an intrinsic property of the Jarid1c locus Nan Lia,b and Laura Carrela,1 aDepartment of Biochemistry and Molecular Biology and bIntercollege Graduate Program in Genetics, Pennsylvania State College of Medicine, Hershey, PA 17033 Edited by Stanley M. Gartler, University of Washington, Seattle, WA, and approved September 23, 2008 (received for review August 8, 2008) Although most genes on one X chromosome in mammalian fe- Sequences on the X are hypothesized to propagate XCI (12) and males are silenced by X inactivation, some ‘‘escape’’ X inactivation to be depleted at escape genes (8, 9). LINE-1 repeats fit such and are expressed from both active and inactive Xs. How these predictions, particularly on the human X (8–10). Distinct dis- escape genes are transcribed from a largely inactivated chromo- tributions of other repeats classify some mouse X genes (5). some is not fully understood, but underlying genomic sequences X-linked transgenes also test the role of genomic sequences in are likely involved. We developed a transgene approach to ask escape gene expression. Most transgenes are X-inactivated, whether an escape locus is autonomous or is instead influenced by although a number escape XCI (e.g., refs. 13 and 14). Such X chromosome location. Two BACs carrying the mouse Jarid1c gene transgene studies indicate that, in addition to CTCF (6), locus and adjacent X-inactivated transcripts were randomly integrated control regions and matrix attachment sites are also not suffi- into mouse XX embryonic stem cells. Four lines with single-copy, cient to escape XCI (15, 16). -
Snapshot: Formins Christian Baarlink, Dominique Brandt, and Robert Grosse University of Marburg, Marburg 35032, Germany
SnapShot: Formins Christian Baarlink, Dominique Brandt, and Robert Grosse University of Marburg, Marburg 35032, Germany Formin Regulators Localization Cellular Function Disease Association DIAPH1/DIA1 RhoA, RhoC Cell cortex, Polarized cell migration, microtubule stabilization, Autosomal-dominant nonsyndromic deafness (DFNA1), myeloproliferative (mDia1) phagocytic cup, phagocytosis, axon elongation defects, defects in T lymphocyte traffi cking and proliferation, tumor cell mitotic spindle invasion, defects in natural killer lymphocyte function DIAPH2 Cdc42 Kinetochore Stable microtubule attachment to kinetochore for Premature ovarian failure (mDia3) chromosome alignment DIAPH3 Rif, Cdc42, Filopodia, Filopodia formation, removing the nucleus from Increased chromosomal deletion of gene locus in metastatic tumors (mDia2) Rac, RhoB, endosomes erythroblast, endosome motility, microtubule DIP* stabilization FMNL1 (FRLα) Cdc42 Cell cortex, Phagocytosis, T cell polarity Overexpression is linked to leukemia and non-Hodgkin lymphoma microtubule- organizing center FMNL2/FRL3/ RhoC ND Cell motility Upregulated in metastatic colorectal cancer, chromosomal deletion is FHOD2 associated with mental retardation FMNL3/FRL2 Constituently Stress fi bers ND ND active DAAM1 Dishevelled Cell cortex Planar cell polarity ND DAAM2 ND ND ND Overexpressed in schizophrenia patients Human (Mouse) FHOD1 ROCK Stress fi bers Cell motility FHOD3 ND Nestin, sarcomere Organizing sarcomeres in striated muscle cells Single-nucleotide polymorphisms associated with type 1 diabetes -
The C9orf72-Interacting Protein Smcr8 Is a Negative Regulator of Autoimmunity and Lysosomal Exocytosis
Downloaded from genesdev.cshlp.org on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press The C9orf72-interacting protein Smcr8 is a negative regulator of autoimmunity and lysosomal exocytosis Yingying Zhang,1,2,3 Aaron Burberry,1,2,3 Jin-Yuan Wang,1,2,3 Jackson Sandoe,1,2,3 Sulagna Ghosh,1,2,3 Namrata D. Udeshi,4 Tanya Svinkina,4 Daniel A. Mordes,1,2,3,5 Joanie Mok,1,2,3 Maura Charlton,1,2,3 Quan-Zhen Li,6,7 Steven A. Carr,4 and Kevin Eggan1,2,3 1Department of Stem Cell and Regenerative Biology, 2Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA; 3Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02142, USA; 4Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA; 5Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA; 6Department of Immunology, 7Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA While a mutation in C9ORF72 is the most common genetic contributor to amyotrophic lateral sclerosis (ALS), much remains to be learned concerning the function of the protein normally encoded at this locus. To elaborate further on functions for C9ORF72, we used quantitative mass spectrometry-based proteomics to identify interacting proteins in motor neurons and found that its long isoform complexes with and stabilizes SMCR8, which further enables interaction with WDR41. To study the organismal and cellular functions for this tripartite complex, we generated Smcr8 loss-of-function mutant mice and found that they developed phenotypes also observed in C9orf72 loss-of- function animals, including autoimmunity. -
Nuclear Organization and the Epigenetic Landscape of the Mus Musculus X-Chromosome Alicia Liu University of Connecticut - Storrs, [email protected]
University of Connecticut OpenCommons@UConn Doctoral Dissertations University of Connecticut Graduate School 8-9-2019 Nuclear Organization and the Epigenetic Landscape of the Mus musculus X-Chromosome Alicia Liu University of Connecticut - Storrs, [email protected] Follow this and additional works at: https://opencommons.uconn.edu/dissertations Recommended Citation Liu, Alicia, "Nuclear Organization and the Epigenetic Landscape of the Mus musculus X-Chromosome" (2019). Doctoral Dissertations. 2273. https://opencommons.uconn.edu/dissertations/2273 Nuclear Organization and the Epigenetic Landscape of the Mus musculus X-Chromosome Alicia J. Liu, Ph.D. University of Connecticut, 2019 ABSTRACT X-linked imprinted genes have been hypothesized to contribute parent-of-origin influences on social cognition. A cluster of imprinted genes Xlr3b, Xlr4b, and Xlr4c, implicated in cognitive defects, are maternally expressed and paternally silent in the murine brain. These genes defy classic mechanisms of autosomal imprinting, suggesting a novel method of imprinted gene regulation. Using Xlr3b and Xlr4c as bait, this study uses 4C-Seq on neonatal whole brain of a 39,XO mouse model, to provide the first in-depth analysis of chromatin dynamics surrounding an imprinted locus on the X-chromosome. Significant differences in long-range contacts exist be- tween XM and XP monosomic samples. In addition, XM interaction profiles contact a greater number of genes linked to cognitive impairment, abnormality of the nervous system, and abnormality of higher mental function. This is not a pattern that is unique to the imprinted Xlr3/4 locus. Additional Alicia J. Liu - University of Connecticut - 2019 4C-Seq experiments show that other genes on the X-chromosome, implicated in intellectual disability and/or ASD, also produce more maternal contacts to other X-linked genes linked to cognitive impairment. -
Defining Functional Interactions During Biogenesis of Epithelial Junctions
ARTICLE Received 11 Dec 2015 | Accepted 13 Oct 2016 | Published 6 Dec 2016 | Updated 5 Jan 2017 DOI: 10.1038/ncomms13542 OPEN Defining functional interactions during biogenesis of epithelial junctions J.C. Erasmus1,*, S. Bruche1,*,w, L. Pizarro1,2,*, N. Maimari1,3,*, T. Poggioli1,w, C. Tomlinson4,J.Lees5, I. Zalivina1,w, A. Wheeler1,w, A. Alberts6, A. Russo2 & V.M.M. Braga1 In spite of extensive recent progress, a comprehensive understanding of how actin cytoskeleton remodelling supports stable junctions remains to be established. Here we design a platform that integrates actin functions with optimized phenotypic clustering and identify new cytoskeletal proteins, their functional hierarchy and pathways that modulate E-cadherin adhesion. Depletion of EEF1A, an actin bundling protein, increases E-cadherin levels at junctions without a corresponding reinforcement of cell–cell contacts. This unexpected result reflects a more dynamic and mobile junctional actin in EEF1A-depleted cells. A partner for EEF1A in cadherin contact maintenance is the formin DIAPH2, which interacts with EEF1A. In contrast, depletion of either the endocytic regulator TRIP10 or the Rho GTPase activator VAV2 reduces E-cadherin levels at junctions. TRIP10 binds to and requires VAV2 function for its junctional localization. Overall, we present new conceptual insights on junction stabilization, which integrate known and novel pathways with impact for epithelial morphogenesis, homeostasis and diseases. 1 National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK. 2 Computing Department, Imperial College London, London SW7 2AZ, UK. 3 Bioengineering Department, Faculty of Engineering, Imperial College London, London SW7 2AZ, UK. 4 Department of Surgery & Cancer, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK. -
82262967.Pdf
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Current Biology 19, 1478–1484, September 15, 2009 ª2009 Elsevier Ltd All rights reserved DOI 10.1016/j.cub.2009.07.041 Report Key Features of the X Inactivation Process Are Conserved between Marsupials and Eutherians Shantha K. Mahadevaiah,1 Helene Royo,1 in situ hybridization (RNA FISH) [1] and semiquantitative John L. VandeBerg,2 John R. McCarrey,3 Sarah Mackay,4 reverse transcriptase-polymerase chain reaction (RT-PCR) and James M.A. Turner1,* [2] have concluded that the X chromosome of the marsupial 1MRC National Institute for Medical Research, Mill Hill, Monodelphis domestica (opossum) remains inactive during London NW7 1AA, UK spermiogenesis. However, Cot-1 RNA FISH has since been 2Department of Genetics, Southwest Foundation for shown to primarily detect silencing of repeat rather than Biomedical Research, San Antonio, TX 78227, USA coding X-linked sequences [16, 17], and RT-PCR cannot 3Department of Biology, University of Texas at San Antonio, discriminate between steady-state RNA levels and ongoing San Antonio, TX 78249, USA transcription. We therefore sought to reexamine male germline 4Division of Integrated Biology, Faculty of Biomedical & Life X silencing and its relationship to female XCI with a gene- Sciences, University of Glasgow, Glasgow G12 8QQ, specific RNA FISH approach. Scotland, UK For our analysis of XCI in the male germline, we selected ten genes distributed across the opossum X chromosome (Fig- ure 1A). We wished to compare X gene silencing in opossum Summary with that in mouse, in which MSCI and its maintenance have been well characterized [18, 19]. -
MBNL1 Regulates Essential Alternative RNA Splicing Patterns in MLL-Rearranged Leukemia
ARTICLE https://doi.org/10.1038/s41467-020-15733-8 OPEN MBNL1 regulates essential alternative RNA splicing patterns in MLL-rearranged leukemia Svetlana S. Itskovich1,9, Arun Gurunathan 2,9, Jason Clark 1, Matthew Burwinkel1, Mark Wunderlich3, Mikaela R. Berger4, Aishwarya Kulkarni5,6, Kashish Chetal6, Meenakshi Venkatasubramanian5,6, ✉ Nathan Salomonis 6,7, Ashish R. Kumar 1,7 & Lynn H. Lee 7,8 Despite growing awareness of the biologic features underlying MLL-rearranged leukemia, 1234567890():,; targeted therapies for this leukemia have remained elusive and clinical outcomes remain dismal. MBNL1, a protein involved in alternative splicing, is consistently overexpressed in MLL-rearranged leukemias. We found that MBNL1 loss significantly impairs propagation of murine and human MLL-rearranged leukemia in vitro and in vivo. Through transcriptomic profiling of our experimental systems, we show that in leukemic cells, MBNL1 regulates alternative splicing (predominantly intron exclusion) of several genes including those essential for MLL-rearranged leukemogenesis, such as DOT1L and SETD1A.Wefinally show that selective leukemic cell death is achievable with a small molecule inhibitor of MBNL1. These findings provide the basis for a new therapeutic target in MLL-rearranged leukemia and act as further validation of a burgeoning paradigm in targeted therapy, namely the disruption of cancer-specific splicing programs through the targeting of selectively essential RNA binding proteins. 1 Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA. 2 Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA. 3 Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA. -
To Study Mutant P53 Gain of Function, Various Tumor-Derived P53 Mutants
Differential effects of mutant TAp63γ on transactivation of p53 and/or p63 responsive genes and their effects on global gene expression. A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science By Shama K Khokhar M.Sc., Bilaspur University, 2004 B.Sc., Bhopal University, 2002 2007 1 COPYRIGHT SHAMA K KHOKHAR 2007 2 WRIGHT STATE UNIVERSITY SCHOOL OF GRADUATE STUDIES Date of Defense: 12-03-07 I HEREBY RECOMMEND THAT THE THESIS PREPARED UNDER MY SUPERVISION BY SHAMA KHAN KHOKHAR ENTITLED Differential effects of mutant TAp63γ on transactivation of p53 and/or p63 responsive genes and their effects on global gene expression BE ACCEPTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF Master of Science Madhavi P. Kadakia, Ph.D. Thesis Director Daniel Organisciak , Ph.D. Department Chair Committee on Final Examination Madhavi P. Kadakia, Ph.D. Steven J. Berberich, Ph.D. Michael Leffak, Ph.D. Joseph F. Thomas, Jr., Ph.D. Dean, School of Graduate Studies 3 Abstract Khokhar, Shama K. M.S., Department of Biochemistry and Molecular Biology, Wright State University, 2007 Differential effect of TAp63γ mutants on transactivation of p53 and/or p63 responsive genes and their effects on global gene expression. p63, a member of the p53 gene family, known to play a role in development, has more recently also been implicated in cancer progression. Mice lacking p63 exhibit severe developmental defects such as limb truncations, abnormal skin, and absence of hair follicles, teeth, and mammary glands. Germline missense mutations of p63 have been shown to be responsible for several human developmental syndromes including SHFM, EEC and ADULT syndromes and are associated with anomalies in the development of organs of epithelial origin. -
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Patterns of DNA methylation on the human X chromosome and use in analyzing X-chromosome inactivation by Allison Marie Cotton B.Sc., The University of Guelph, 2005 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in The Faculty of Graduate Studies (Medical Genetics) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) January 2012 © Allison Marie Cotton, 2012 Abstract The process of X-chromosome inactivation achieves dosage compensation between mammalian males and females. In females one X chromosome is transcriptionally silenced through a variety of epigenetic modifications including DNA methylation. Most X-linked genes are subject to X-chromosome inactivation and only expressed from the active X chromosome. On the inactive X chromosome, the CpG island promoters of genes subject to X-chromosome inactivation are methylated in their promoter regions, while genes which escape from X- chromosome inactivation have unmethylated CpG island promoters on both the active and inactive X chromosomes. The first objective of this thesis was to determine if the DNA methylation of CpG island promoters could be used to accurately predict X chromosome inactivation status. The second objective was to use DNA methylation to predict X-chromosome inactivation status in a variety of tissues. A comparison of blood, muscle, kidney and neural tissues revealed tissue-specific X-chromosome inactivation, in which 12% of genes escaped from X-chromosome inactivation in some, but not all, tissues. X-linked DNA methylation analysis of placental tissues predicted four times higher escape from X-chromosome inactivation than in any other tissue. Despite the hypomethylation of repetitive elements on both the X chromosome and the autosomes, no changes were detected in the frequency or intensity of placental Cot-1 holes. -
The Role of Structural Disorder in Cell Cycle Regulation, Related Clinical Proteomics, 5 Disease Development and Drug Targeting
Review The role of structural disorder in cell cycle regulation, related clinical proteomics, 5 disease development and drug targeting Expert Rev. Proteomics 12(3), 000–000 (2015) 10 1 AQ2 Agnes Tantos , Understanding the molecular mechanisms of the regulation of cell cycle is a central issue in Lajos Kalmar2 and molecular cell biology, due to its fundamental role in the existence of cells. The regulatory Peter Tompa*1,2 circuits that make decisions on when a cell should divide are very complex and particularly subtly balanced in eukaryotes, in which the harmony of many different cells in an organism is 1 Institute of Enzymology, Research essential for life. Several hundred proteins are involved in these processes, and a great deal of 15 Centre for Natural Sciences of the Hungarian Academy of Sciences, studies attests that most of them have functionally relevant intrinsic structural disorder. Budapest, Hungary Structural disorder imparts many functional advantages on these proteins, and we discuss it 2 VIB Department of Structural Biology, in detail that it is involved in all key steps from signaling through the cell membrane to Vrije Universiteit Brussel, Brussels, Belgium regulating transcription of proteins that execute timely responses to an ever-changing *Author for correspondence: environment. 20 [email protected] KEYWORDS: cancer . cell-cycle . checkpoint . post-translational modification . protein disorder . signal transduction 25 of proteins are able to fulfill important func- Cell cycle: the cornerstone of tions without possessing a stable three- multicellular life dimensional structure [3,4]. These proteins, Every postembryonic eukaryotic cell goes termed intrinsically disordered proteins or through the distinct phases of cell cycle, regions (IDPs/IDRs), participate in many reg- G1, S, G2 and M.