Mitochondrial Biogenesis Through Activation of Nuclear Signaling Proteins
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Analysis of Trans Esnps Infers Regulatory Network Architecture
Analysis of trans eSNPs infers regulatory network architecture Anat Kreimer Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2014 © 2014 Anat Kreimer All rights reserved ABSTRACT Analysis of trans eSNPs infers regulatory network architecture Anat Kreimer eSNPs are genetic variants associated with transcript expression levels. The characteristics of such variants highlight their importance and present a unique opportunity for studying gene regulation. eSNPs affect most genes and their cell type specificity can shed light on different processes that are activated in each cell. They can identify functional variants by connecting SNPs that are implicated in disease to a molecular mechanism. Examining eSNPs that are associated with distal genes can provide insights regarding the inference of regulatory networks but also presents challenges due to the high statistical burden of multiple testing. Such association studies allow: simultaneous investigation of many gene expression phenotypes without assuming any prior knowledge and identification of unknown regulators of gene expression while uncovering directionality. This thesis will focus on such distal eSNPs to map regulatory interactions between different loci and expose the architecture of the regulatory network defined by such interactions. We develop novel computational approaches and apply them to genetics-genomics data in human. We go beyond pairwise interactions to define network motifs, including regulatory modules and bi-fan structures, showing them to be prevalent in real data and exposing distinct attributes of such arrangements. We project eSNP associations onto a protein-protein interaction network to expose topological properties of eSNPs and their targets and highlight different modes of distal regulation. -
AMPK, Mitochondrial Function, and Cardiovascular Disease
International Journal of Molecular Sciences Review AMPK, Mitochondrial Function, and Cardiovascular Disease Shengnan Wu * and Ming-Hui Zou Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA 30303, USA; [email protected] * Correspondence: [email protected] Received: 11 June 2020; Accepted: 6 July 2020; Published: 15 July 2020 Abstract: Adenosine monophosphate-activated protein kinase (AMPK) is in charge of numerous catabolic and anabolic signaling pathways to sustain appropriate intracellular adenosine triphosphate levels in response to energetic and/or cellular stress. In addition to its conventional roles as an intracellular energy switch or fuel gauge, emerging research has shown that AMPK is also a redox sensor and modulator, playing pivotal roles in maintaining cardiovascular processes and inhibiting disease progression. Pharmacological reagents, including statins, metformin, berberine, polyphenol, and resveratrol, all of which are widely used therapeutics for cardiovascular disorders, appear to deliver their protective/therapeutic effects partially via AMPK signaling modulation. The functions of AMPK during health and disease are far from clear. Accumulating studies have demonstrated crosstalk between AMPK and mitochondria, such as AMPK regulation of mitochondrial homeostasis and mitochondrial dysfunction causing abnormal AMPK activity. In this review, we begin with the description of AMPK structure and regulation, and then focus on the recent advances toward understanding how mitochondrial dysfunction controls AMPK and how AMPK, as a central mediator of the cellular response to energetic stress, maintains mitochondrial homeostasis. Finally, we systemically review how dysfunctional AMPK contributes to the initiation and progression of cardiovascular diseases via the impact on mitochondrial function. Keywords: mitochondrial function; AMPK; cardiovascular disease 1. Introduction Cells constantly coordinate their metabolism to satisfy their energy needs and respond to the use of nutrients. -
Cytotoxic Effects and Changes in Gene Expression Profile
Toxicology in Vitro 34 (2016) 309–320 Contents lists available at ScienceDirect Toxicology in Vitro journal homepage: www.elsevier.com/locate/toxinvit Fusarium mycotoxin enniatin B: Cytotoxic effects and changes in gene expression profile Martina Jonsson a,⁎,MarikaJestoib, Minna Anthoni a, Annikki Welling a, Iida Loivamaa a, Ville Hallikainen c, Matti Kankainen d, Erik Lysøe e, Pertti Koivisto a, Kimmo Peltonen a,f a Chemistry and Toxicology Research Unit, Finnish Food Safety Authority (Evira), Mustialankatu 3, FI-00790 Helsinki, Finland b Product Safety Unit, Finnish Food Safety Authority (Evira), Mustialankatu 3, FI-00790 Helsinki, c The Finnish Forest Research Institute, Rovaniemi Unit, P.O. Box 16, FI-96301 Rovaniemi, Finland d Institute for Molecular Medicine Finland (FIMM), University of Helsinki, P.O. Box 20, FI-00014, Finland e Plant Health and Biotechnology, Norwegian Institute of Bioeconomy, Høyskoleveien 7, NO -1430 Ås, Norway f Finnish Safety and Chemicals Agency (Tukes), Opastinsilta 12 B, FI-00521 Helsinki, Finland article info abstract Article history: The mycotoxin enniatin B, a cyclic hexadepsipeptide produced by the plant pathogen Fusarium,isprevalentin Received 3 December 2015 grains and grain-based products in different geographical areas. Although enniatins have not been associated Received in revised form 5 April 2016 with toxic outbreaks, they have caused toxicity in vitro in several cell lines. In this study, the cytotoxic effects Accepted 28 April 2016 of enniatin B were assessed in relation to cellular energy metabolism, cell proliferation, and the induction of ap- Available online 6 May 2016 optosis in Balb 3T3 and HepG2 cells. The mechanism of toxicity was examined by means of whole genome ex- fi Keywords: pression pro ling of exposed rat primary hepatocytes. -
Estradiol Stimulates Mitochondrial Biogenesis and Adiponectin Expression in Skeletal Muscle
G CAPLLONCH-AMER and others Mitochondrial biogenesis 221:3 391–403 Research stimulation in WGM Estradiol stimulates mitochondrial biogenesis and adiponectin expression in skeletal muscle Gabriela Capllonch-Amer1, Miquel Sbert-Roig1, Bel M Galme´s-Pascual1, Ana M Proenza1,2, Isabel Llado´1,2, Magdalena Gianotti1,2 and Francisco J Garcı´a-Palmer1,2 1Grup Metabolisme Energe` tic i Nutricio´ , Departament de Biologia Fonamental i Cie` ncies de la Salut, Institut Correspondence Universitari d’Investigacio´ en Cie` ncies de la Salut (IUNICS), Universitat de les Illes Balears, Ctra. Valldemossa, should be addressed km 7,5. E-07122 Palma de Mallorca, Illes Balears, Spain to M Gianotti 2Centro de Investigacio´ n Biome´ dica en Red Fisiopatologı´a de la Obesidad y la Nutricio´ n (CIBERobn, CB06/03/0043), Email Instituto de Salud Carlos III, Madrid, Spain [email protected] Abstract Sexual dimorphism has been found in mitochondrial features of skeletal muscle, with female Key Words rats showing greater mitochondrial mass and function compared with males. Adiponectin is an " 17b-estradiol insulin-sensitizing adipokine whose expression has been related to mitochondrial function and " testosterone that is also expressed in skeletal muscle, where it exerts local metabolic effects. The aim of this " ovariectomy research was to elucidate the role of sex hormones in modulation of mitochondrial function, as " mitochondrial biogenesis well as its relationship with adiponectin production in rat skeletal muscle. An in vivo study with " mitochondrial dynamics ovariectomized Wistar rats receiving or not receiving 17b-estradiol (E2)(10mg/kg per 48 h for " skeletal muscle Journal of Endocrinology 4 weeks) was carried out, in parallel with an assay of cultured myotubes (L6E9) treated with " adiponectin E2 (10 nM), progesterone (Pg; 1 mM), or testosterone (1 mM). -
Role and Regulation of the P53-Homolog P73 in the Transformation of Normal Human Fibroblasts
Role and regulation of the p53-homolog p73 in the transformation of normal human fibroblasts Dissertation zur Erlangung des naturwissenschaftlichen Doktorgrades der Bayerischen Julius-Maximilians-Universität Würzburg vorgelegt von Lars Hofmann aus Aschaffenburg Würzburg 2007 Eingereicht am Mitglieder der Promotionskommission: Vorsitzender: Prof. Dr. Dr. Martin J. Müller Gutachter: Prof. Dr. Michael P. Schön Gutachter : Prof. Dr. Georg Krohne Tag des Promotionskolloquiums: Doktorurkunde ausgehändigt am Erklärung Hiermit erkläre ich, dass ich die vorliegende Arbeit selbständig angefertigt und keine anderen als die angegebenen Hilfsmittel und Quellen verwendet habe. Diese Arbeit wurde weder in gleicher noch in ähnlicher Form in einem anderen Prüfungsverfahren vorgelegt. Ich habe früher, außer den mit dem Zulassungsgesuch urkundlichen Graden, keine weiteren akademischen Grade erworben und zu erwerben gesucht. Würzburg, Lars Hofmann Content SUMMARY ................................................................................................................ IV ZUSAMMENFASSUNG ............................................................................................. V 1. INTRODUCTION ................................................................................................. 1 1.1. Molecular basics of cancer .......................................................................................... 1 1.2. Early research on tumorigenesis ................................................................................. 3 1.3. Developing -
Blood-Derived Mitochondrial DNA Copy Number Is Associated with Gene Expression Across Multiple
bioRxiv preprint doi: https://doi.org/10.1101/2020.07.17.209023; this version posted July 18, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Blood-derived mitochondrial DNA copy number is associated with gene expression across multiple 2 tissues and is predictive for incident neurodegenerative disease 3 4 Stephanie Y. Yang1, Christina A. Castellani1, Ryan J. Longchamps1, Vamsee K. Pillalamarri1, Brian 5 O’Rourke2, Eliseo Guallar3, Dan E. Arking1,2 6 7 8 1McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, 9 Baltimore, MD 10 2Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, 11 Baltimore, MD 12 3Departments of Epidemiology and Medicine, and Welch Center for Prevention, Epidemiology, and 13 Clinical Research, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 14 15 Email addresses: 16 [email protected] 17 [email protected] 18 [email protected] 19 [email protected] 20 [email protected] 21 [email protected] 22 [email protected] 23 24 25 26 27 28 29 30 31 32 33 34 35 *Correspondence and address for reprints to: 36 Dan E. Arking, Ph.D. 37 Johns Hopkins University School of Medicine 38 733 N Broadway Ave 39 Miller Research Building Room 459 40 Baltimore, MD 21205 41 (410) 502-4867 (ph) 42 [email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.07.17.209023; this version posted July 18, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. -
Human Mitochondrial Transcription Factors TFAM and TFB2M Work Synergistically in Promoter Melting During Transcription Initiatio
Published online 28 November 2016 Nucleic Acids Research, 2017, Vol. 45, No. 2 861–874 doi: 10.1093/nar/gkw1157 Human mitochondrial transcription factors TFAM and TFB2M work synergistically in promoter melting during transcription initiation Aparna Ramachandran1, Urmimala Basu1,2, Shemaila Sultana1, Divya Nandakumar1 and Smita S. Patel1,* 1Department of Biochemistry and Molecular Biology, Rutgers, Robert Wood Johnson Medical school, Piscataway, NJ 08854, USA and 2Graduate School of Biomedical Sciences, Rutgers University, Piscataway, NJ 08854, USA Received August 10, 2016; Revised November 02, 2016; Editorial Decision November 04, 2016; Accepted November 04, 2016 ABSTRACT is transcribed by POLRMT, which is homologous to single subunit RNA polymerases from phage T7 and yeast mito- Human mitochondrial DNA is transcribed by POL- chondria (3). T7 RNA polymerase can initiate transcription RMT with the help of two initiation factors, TFAM on its own without any transcription factors (4), the Sac- and TFB2M. The current model postulates that the charomyces cerevisiae Rpo41 requires Mtf1 to initiate tran- role of TFAM is to recruit POLRMT and TFB2M to scription (5–7), and the human POLRMT requires two ini- melt the promoter. However, we show that TFAM tiation factors, TFAM (Transcription Factor A of the Mi- has ‘post-recruitment’ roles in promoter melting and tochondria) and TFB2M (Transcription Factor B2 of the RNA synthesis, which were revealed by studying Mitochondria) for transcript synthesis (8,9). the pre-initiation steps of promoter binding, bend- The initiation factor TFB2M is structurally homologous ing and melting, and abortive RNA synthesis. Our to bacterial RNA methyltransferase ErmC’ (8,10); how- 2-aminopurine mapping studies show that the LSP ever, it has lost most of its RNA methyltransferase activity (11) and serves mainly as the transcription initiation fac- (Light Strand Promoter) is melted from −4to+1in − tor. -
A High-Throughput Approach to Uncover Novel Roles of APOBEC2, a Functional Orphan of the AID/APOBEC Family
Rockefeller University Digital Commons @ RU Student Theses and Dissertations 2018 A High-Throughput Approach to Uncover Novel Roles of APOBEC2, a Functional Orphan of the AID/APOBEC Family Linda Molla Follow this and additional works at: https://digitalcommons.rockefeller.edu/ student_theses_and_dissertations Part of the Life Sciences Commons A HIGH-THROUGHPUT APPROACH TO UNCOVER NOVEL ROLES OF APOBEC2, A FUNCTIONAL ORPHAN OF THE AID/APOBEC FAMILY A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy by Linda Molla June 2018 © Copyright by Linda Molla 2018 A HIGH-THROUGHPUT APPROACH TO UNCOVER NOVEL ROLES OF APOBEC2, A FUNCTIONAL ORPHAN OF THE AID/APOBEC FAMILY Linda Molla, Ph.D. The Rockefeller University 2018 APOBEC2 is a member of the AID/APOBEC cytidine deaminase family of proteins. Unlike most of AID/APOBEC, however, APOBEC2’s function remains elusive. Previous research has implicated APOBEC2 in diverse organisms and cellular processes such as muscle biology (in Mus musculus), regeneration (in Danio rerio), and development (in Xenopus laevis). APOBEC2 has also been implicated in cancer. However the enzymatic activity, substrate or physiological target(s) of APOBEC2 are unknown. For this thesis, I have combined Next Generation Sequencing (NGS) techniques with state-of-the-art molecular biology to determine the physiological targets of APOBEC2. Using a cell culture muscle differentiation system, and RNA sequencing (RNA-Seq) by polyA capture, I demonstrated that unlike the AID/APOBEC family member APOBEC1, APOBEC2 is not an RNA editor. Using the same system combined with enhanced Reduced Representation Bisulfite Sequencing (eRRBS) analyses I showed that, unlike the AID/APOBEC family member AID, APOBEC2 does not act as a 5-methyl-C deaminase. -
TFB2M (NM 022366) Human Untagged Clone – SC112537
OriGene Technologies, Inc. 9620 Medical Center Drive, Ste 200 Rockville, MD 20850, US Phone: +1-888-267-4436 [email protected] EU: [email protected] CN: [email protected] Product datasheet for SC112537 TFB2M (NM_022366) Human Untagged Clone Product data: Product Type: Expression Plasmids Product Name: TFB2M (NM_022366) Human Untagged Clone Tag: Tag Free Symbol: TFB2M Synonyms: Hkp1; mtTFB2 Vector: pCMV6-XL5 E. coli Selection: Ampicillin (100 ug/mL) Cell Selection: None Fully Sequenced ORF: >OriGene ORF within SC112537 sequence for NM_022366 edited (data generated by NextGen Sequencing) ATGTGGATCCCAGTGGTCGGGCTTCCTCGGCGGCTGAGGCTCTCCGCCTTGGCGGGCGCT GGTCGCTTTTGCATTTTAGGGTCTGAAGCGGCGACGCGAAAGCATTTGCCGGCGAGGAAC CACTGTGGGCTCTCTGACTCCTCTCCGCAGCTGTGGCCCGAACCGGATTTCAGGAATCCG CCAAGGAAGGCGTCTAAGGCCAGCTTAGACTTTAAGCGTTACGTAACCGATCGGAGATTG GCTGAGACCCTGGCGCAAATCTATTTGGGAAAACCAAGTAGACCTCCACACCTACTGCTG GAGTGCAATCCAGGTCCTGGAATCCTGACTCAGGCATTACTTGAAGCTGGTGCCAAAGTG GTTGCGCTCGAAAGTGACAAAACTTTTATTCCACATTTGGAGTCCTTAGGAAAAAATCTG GATGGAAAACTACGAGTGATTCACTGTGACTTCTTTAAACTAGATCCTAGAAGTGGTGGA GTAATAAAACCACCTGCTATGTCTTCTCGAGGGCTCTTTAAGAATTTGGGAATAGAAGCA GTTCCTTGGACAGCAGACATCCCTTTAAAAGTAGTTGGAATGTTCCCAAGTAGAGGTGAG AAAAGGGCACTTTGGAAACTCGCATATGACTTGTATTCCTGTACTTCTATATATAAATTT GGACGAATAGAAGTAAATATGTTTATTGGTGAAAAAGAATTCCAGAAACTAATGGCAGAT CCCGGAAATCCAGACTTGTATCATGTATTAAGTGTTATCTGGCAATTAGCTTGTGAGATT AAGGTTCTGCACATGGAGCCTTGGTCATCATTTGATATATACACCCGGAAAGGGCCGCTG GAAAACCCAAAGCGTAGGGAATTATTAGACCAATTACAACAAAAGCTGTATCTTATTCAA ATGATTCCTCGTCAAAATTTATTTACCAAGAACTTAACACCTATGAACTATAATATATTT -
Transcriptional Regulatory Circuits Controlling Mitochondrial Biogenesis and Function
Downloaded from genesdev.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Transcriptional regulatory circuits controlling mitochondrial biogenesis and function Daniel P. Kelly1,3 and Richard C. Scarpulla2 1Center for Cardiovascular Research, Departments of Medicine, Molecular Biology & Pharmacology, and Pediatrics, Washington University School of Medicine, St.Louis, Missouri 63119, USA ; 2Department of Cell and Molecular Biology, Northwestern Medical School, Chicago, Illinois 60611, USA We are witnessing a period of renewed interest in the The limited coding capacity of mtDNA necessitates biology of the mitochondrion.The mitochondrion serves that nuclear genes make a major contribution to mito- a critical function in the maintenance of cellular energy chondrial metabolic systems and molecular architecture stores, thermogenesis, and apoptosis.Moreover, alter- (Garesse and Vallejo 2001).One major class of nuclear ations in mitochondrial function contribute to several genes contributes catalytic and auxiliary proteins to the inherited and acquired human diseases and the aging mitochondrial enzyme systems.For example, the major- process.This review summarizes our understanding of ity of the 100 or so subunits of the respiratory apparatus the transcriptional regulatory mechanisms involved in are nucleus-encoded.In addition, nucleus-encoded meta- the biogenesis and energy metabolic function of mito- bolic enzymes necessary for the oxidation of pyruvate, chondria in higher organisms. fatty acids (-oxidation -
UC San Diego Electronic Theses and Dissertations
UC San Diego UC San Diego Electronic Theses and Dissertations Title Cardiac Stretch-Induced Transcriptomic Changes are Axis-Dependent Permalink https://escholarship.org/uc/item/7m04f0b0 Author Buchholz, Kyle Stephen Publication Date 2016 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California UNIVERSITY OF CALIFORNIA, SAN DIEGO Cardiac Stretch-Induced Transcriptomic Changes are Axis-Dependent A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Bioengineering by Kyle Stephen Buchholz Committee in Charge: Professor Jeffrey Omens, Chair Professor Andrew McCulloch, Co-Chair Professor Ju Chen Professor Karen Christman Professor Robert Ross Professor Alexander Zambon 2016 Copyright Kyle Stephen Buchholz, 2016 All rights reserved Signature Page The Dissertation of Kyle Stephen Buchholz is approved and it is acceptable in quality and form for publication on microfilm and electronically: Co-Chair Chair University of California, San Diego 2016 iii Dedication To my beautiful wife, Rhia. iv Table of Contents Signature Page ................................................................................................................... iii Dedication .......................................................................................................................... iv Table of Contents ................................................................................................................ v List of Figures ................................................................................................................... -
Mitochondria-Localized AMPK Responds to Local Energetics and Contributes to Exercise and Energetic Stress-Induced Mitophagy
Mitochondria-localized AMPK responds to local energetics and contributes to exercise and energetic stress-induced mitophagy Joshua C. Drakea,b,1, Rebecca J. Wilsona,c, Rhianna C. Lakera, Yuntian Guana,d, Hannah R. Spauldinga, Anna S. Nichenkob, Wenqing Shena, Huayu Shanga, Maya V. Dorna, Kian Huanga, Mei Zhanga,e, Aloka B. Bandarab, Matthew H. Brisendineb, Jennifer A. Kashatusf, Poonam R. Sharmag, Alexander Younga, Jitendra Gautamh, Ruofan Caoi, Horst Wallrabei,j, Paul A. Changk, Michael Wongk, Eric M. Desjardinsl,m, Simon A. Hawleyn, George J. Christg,o, David F. Kashatusf, Clint L. Millerc,g,p,q, Matthew J. Wolfa,e, Ammasi Periasamyi,j, Gregory R. Steinbergl,r, D. Grahame Hardien, and Zhen Yana,d,e,s,1 aCenter for Skeletal Muscle Research at Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville,VA 22908; bDepartment of Human Nutrition, Foods, and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061; cDepartment of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22908; dDepartment of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908; eDepartment of Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908; fDepartment of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA 22908; gDepartment of Biomedical Engineering, University of Virginia School of Medicine, Charlottesville, VA 22908; hDepartment