DOCSLIB.ORG

Helix Unwinding and Base Flipping Enable Human MTERF1 to Terminate Mitochondrial Transcription

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Helix Unwinding and Base Flipping Enable Human MTERF1 to Terminate Mitochondrial Transcription Helix Unwinding and Base Flipping Enable Human MTERF1 to Terminate Mitochondrial Transcription Elena Yakubovskaya,1,2 Edison Mejia,1,2 James Byrnes,1 Elena Hambardjieva,1 and Miguel Garcia-Diaz1,* 1Department of Pharmacological Sciences. Stony Brook University. BST 7-169. Stony Brook, NY 11794, USA 2These authors contributed equally to this work *Correspondence: [email protected] DOI 10.1016/j.cell.2010.05.018 SUMMARY instance in response to estrogen (Klinge, 2008). In addition, mito- chondria contain their own family of dedicated transcriptional Defects in mitochondrial gene expression are associ- regulators: the mterf proteins. The mterf (for mitochondrial ated with aging and disease. Mterf proteins have termination factor) family of proteins contains four members been implicated in modulating transcription, replica- (MTERF1–4) all of which share homology to MTERF1, a protein tion and protein synthesis. We have solved the originally identified as a factor responsible for mitochondrial structure of a member of this family, the human mito- transcriptional termination. These proteins have been implicated chondrial transcriptional terminator MTERF1, bound in mitochondrial transcription, the coordination between tran- scription and replication and the regulation of mitochondrial to dsDNA containing the termination sequence. The protein synthesis (Linder et al., 2005; Park et al., 2007; Roberti structure indicates that upon sequence recognition et al., 2009; Pellegrini et al., 2009). MTERF1 is the canonical MTERF1 unwinds the DNA molecule, promoting transcriptional terminator and was originally identified as eversion of three nucleotides. Base flipping is critical a factor responsible for terminating heavy strand transcription for stable binding and transcriptional termination. at a specific site at the leu-tRNA (Kruse et al., 1989), thereby Additional structural and biochemical results provide modulating the ratio of mitochondrial ribosomal RNA to mRNA insight into the DNA binding mechanism and explain (Roberti et al., 2009). It was later shown that in this context, how MTERF1 recognizes its target sequence. Finally, besides acting as a termination factor, MTERF1 appears to be we have demonstrated that the mitochondrial patho- capable of stimulating transcriptional initiation (Martin et al., genic G3249A and G3244A mutations interfere with 2005). Moreover, it has been proposed that MTERF1 can key interactions for sequence recognition, elimi- mediate the formation of a loop in mitochondrial DNA to promote efficient rRNA synthesis (Martin et al., 2005), although the ability nating termination. Our results provide insight into of MTERF1 to bind to the HSP region is controversial (Park et al., the role of mterf proteins and suggest a link between 2007). Like other mterf proteins, MTERF1 appears to be multi- mitochondrial disease and the regulation of mito- functional, and a recent report has implicated it in the control chondrial transcription. of mitochondrial replication pausing (Hyva¨ rinen et al., 2007). All these observations are however based on in vitro experiments, INTRODUCTION and no in vivo evidence exists to support any of these proposed roles. Interestingly, the pathogenic A3243G MELAS mutation Mitochondrial transcription is responsible for expression of 13 was shown to decrease the ability of MTERF1 to terminate proteins encoded in the mitochondrial DNA as well as synthesis transcription in vitro (Hess et al., 1991) and yet no obvious tran- of two rRNAs and 22 tRNAs (Anderson et al., 1981). Transcription scriptional alterations are observed in cells carrying this MELAS originates from two promoters located in the regulatory D loop, mutation (Chomyn et al., 1992). A lack of structural information a heavy strand and a light strand promoter (HSP and LSP), that on this family of proteins has contributed to maintain these are responsible for transcription of the heavy and light strands, uncertainties about their cellular role. Sequence alignments led respectively (Asin-Cayuela and Gustafsson, 2007; Gaspari et al., to the suggestion that they are modular leucine-zipper contain- 2004; Scarpulla, 2008). Initiation is dependent on the RNA poly- ing proteins (Fernandez-Silva et al., 1997; Roberti et al., 2006), merase, POLRMT, and two transcription factors, TFAM and and that has been suggested to be the basis of their ability to TFB2M (Sologub et al., 2009; Metodiev et al., 2009), while bind DNA (Roberti et al., 2009). POLRMT is sufficient for elongation. Hence, mitochondrial tran- In this paper, we have structurally characterized MTERF1 scription can be regulated by modulating the expression of the bound to its recognition sequence in the leucine tRNA and genes responsible for the process itself (Scarpulla, 2006; Hock have analyzed its mechanism of binding. Our results unexpect- and Kralli, 2009), but some evidence suggests that transcrip- edly show that MTERF1 does not bind DNA via leucine-zippers, tional regulation can occur within the mitochondria as well, for but rather promotes transcriptional termination through a novel 982 Cell 141, 982–993, June 11, 2010 ª2010 Elsevier Inc. A B Figure 1. MTERF1 Is a Modular Protein (A) Amino acid alignment of MTERF1 proteins in different species. Invariant residues are white over a black background. Conserved residues are bold. The numbering corresponds to human MTERF1. Asterisks indicate residues that stack with everted nucleotides and dots indicate resi- dues involved in sequence recognition. Horizontal black bars represent a helices and dotted lines represent 310 helices. Hs, Homo sapiens; fc, felis catus; ss, sus scrofa; ec, equus caballus; bt, bos taurus; mm, Mus musculus; rn, rattus norvegicus; oa, ornithorhynchus anatinus; dr, danio rerio. (B) Overview of the MTERF1 fold. The structure is shown in the absence of DNA. Mterf motifs are color coded as in (A). (C) Overlay of the 8 mterf motifs. The rmsd between the first (transparent red, ribbon repre- sentation) and each of the other repeats ranges between 1.0 and 3.3 A˚ for 24 C-a atoms (the C D average is 2.5 A˚ ). Each repeat is color coded as in (B). (D) Hydrophobic interactions stabilize each mterf repeat. The second mterf motif is shown in ribbon representation. The hydrophobic residues are shown in ball-and-stick representation with their Van der Waals surface in yellow. See also Figure S1. DNA binding mode. Additionally, they provide insight into how diffracted to 2.2A˚ and contained one molecule of MTERF1 bound MTERF1 achieves sequence recognition, and provides clues to to DNA in the asymmetric unit. The final density was of sufficient understand the biological roles of mterf family proteins. We quality to build most of the protein (residues 73 to 396; Figure 1 have also analyzed a number of pathogenic mitochondrial DNA and Figure S1 available online) and all 22 base pairs of DNA. mutations for their ability to interfere with MTERF1 binding and transcriptional termination. We have shown that two mutations, Overall Structure G3249A that causes a variant of Kearns-Sayre syndrome MTERF1 adopts a fold that is very different from previously (Seneca et al., 2001) and G3242A that is associated with an proposed models (Fernandez-Silva et al., 1997; Figure 1B). uncharacterized mitochondrial disorder (Mimaki et al., 2009), Consistent with predictions based on its primary sequence interfere with protein-DNA interactions that are key for sequence (Fernandez-Silva et al., 1997; Roberti et al., 2006), MTERF1 recognition by MTERF1 and as a consequence eliminate its displays a modular architecture. Dali (Holm et al., 2008) and De- transcriptional termination activity. jaVu (Kleywegt and Jones, 1997) were unable to identify signifi- cant structural homology with any protein in the PDB. MTERF1 RESULTS AND DISCUSSION is an all-a-helical protein composed of 19 a helices and 7 310 helices that is structured around a motif (two a helices followed Structural Determination by a 310 helix; hence referred to as the mterf motif) that is In order to investigate how MTERF1 is able to recognize specific repeated throughout the structure (Figure 1B). This structural sequences in the mitochondrial genome as well as the mecha- arrangement is remarkably similar to that seen in other all-alpha nism by which it can modulate transcription we decided to helical regions of proteins such as repeats of armadillo (ARM), crystallize the full-length human protein (minus the N-terminal HEAT (Groves and Barford, 1999) and PUM/PUF motifs (Lu mitochondrial localization sequence; Figure 1A) bound to the et al., 2009). In all these cases the protein fold consists of leu-tRNA sequence responsible for termination of transcription a number of repeats of more or less conserved a-helical motifs. to which MTERF1 binds with high affinity (Nam and Kang, Interestingly, PUM/PUF motifs are the basis of RNA binding in 2005). We expressed and purified human MTERF1 from E. coli PUMILIO proteins (Lu et al., 2009) while the HEAT motifs in cells and obtained crystals of the protein in complex with a DNA PK-cs have been suggested to play a role in double 22-mer double stranded substrate (residues 3232–3253 of the stranded DNA binding (Sibanda et al., 2010). human mitochondrial DNA). In order to solve the structure taking The MTERF1 fold contains 8 mterf motifs and an additional advantage of Multiwavelength Anomalous Dispersion phasing distorted motif in the C terminus (Figure 1C). Within each motif, (Hendrickson and Ogata, 1997) we also crystallized MTERF1 in several hydrophobic residues create
Load more

Recommended publications
  • 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]
  • A Divergent Pumilio Repeat Protein Family for Pre-Rrna Processing and Mrna Localization
    A divergent Pumilio repeat protein family for pre-rRNA processing and mRNA localization Chen Qiua, Kathleen L. McCannb, Robert N. Winea, Susan J. Basergab,c,d,1, and Traci M. Tanaka Halla,1 aEpigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709; and Departments of bGenetics, cMolecular Biophysics and Biochemistry, and dTherapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520 Edited by David Baker, University of Washington, Seattle, WA, and approved November 19, 2014 (received for review April 25, 2014) Pumilio/feminization of XX and XO animals (fem)-3 mRNA-binding cell (15). In addition to these functional differences, it is unclear factor (PUF) proteins bind sequence specifically to mRNA targets how these new PUM repeat proteins would interact with target using a single-stranded RNA-binding domain comprising eight RNA. For example, only six PUM repeats are predicted in Puf-A Pumilio (PUM) repeats. PUM repeats have now been identified in and Puf6, and their RNA base-interacting residues are poorly proteins that function in pre-rRNA processing, including human conserved. Puf-A and yeast Puf6. This is a role not previously ascribed to PUF Vertebrate Puf-A functions appear to be important for diseases proteins. Here we present crystal structures of human Puf-A that and embryonic development, but more knowledge is needed to reveal a class of nucleic acid-binding proteins with 11 PUM repeats connect vertebrate morbidities with molecular mechanisms. Human arranged in an “L”-like shape. In contrast to classical PUF proteins, Puf-A changes localization from predominantly nucleolar to nu- Puf-A forms sequence-independent interactions with DNA or RNA, clear when cells are treated with transcriptional or topoisomerase mediated by conserved basic residues.
    [Show full text]
  • Mitochondrial Genetics
    Mitochondrial genetics Patrick Francis Chinnery and Gavin Hudson* Institute of Genetic Medicine, International Centre for Life, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK Introduction: In the last 10 years the field of mitochondrial genetics has widened, shifting the focus from rare sporadic, metabolic disease to the effects of mitochondrial DNA (mtDNA) variation in a growing spectrum of human disease. The aim of this review is to guide the reader through some key concepts regarding mitochondria before introducing both classic and emerging mitochondrial disorders. Sources of data: In this article, a review of the current mitochondrial genetics literature was conducted using PubMed (http://www.ncbi.nlm.nih.gov/pubmed/). In addition, this review makes use of a growing number of publically available databases including MITOMAP, a human mitochondrial genome database (www.mitomap.org), the Human DNA polymerase Gamma Mutation Database (http://tools.niehs.nih.gov/polg/) and PhyloTree.org (www.phylotree.org), a repository of global mtDNA variation. Areas of agreement: The disruption in cellular energy, resulting from defects in mtDNA or defects in the nuclear-encoded genes responsible for mitochondrial maintenance, manifests in a growing number of human diseases. Areas of controversy: The exact mechanisms which govern the inheritance of mtDNA are hotly debated. Growing points: Although still in the early stages, the development of in vitro genetic manipulation could see an end to the inheritance of the most severe mtDNA disease. Keywords: mitochondria/genetics/mitochondrial DNA/mitochondrial disease/ mtDNA Accepted: April 16, 2013 Mitochondria *Correspondence address. The mitochondrion is a highly specialized organelle, present in almost all Institute of Genetic Medicine, International eukaryotic cells and principally charged with the production of cellular Centre for Life, Newcastle energy through oxidative phosphorylation (OXPHOS).
    [Show full text]
  • Pathological Ribonuclease H1 Causes R-Loop Depletion and Aberrant DNA Segregation in Mitochondria
    Pathological ribonuclease H1 causes R-loop depletion PNAS PLUS and aberrant DNA segregation in mitochondria Gokhan Akmana,1, Radha Desaia,1, Laura J. Baileyb, Takehiro Yasukawab,2, Ilaria Dalla Rosaa, Romina Durigona, J. Bradley Holmesb,c, Chloe F. Mossa, Mara Mennunia, Henry Houldend, Robert J. Crouchc, Michael G. Hannad, Robert D. S. Pitceathlyd,e, Antonella Spinazzolaa,3, and Ian J. Holta,3 aMedical Research Council, Mill Hill Laboratory, London NW7 1AA, United Kingdom; bMedical Research Council Mitochondrial Biology Unit, Cambridge CB1 9SY, United Kingdom; cDivision of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892; dMedical Research Council Centre for Neuromuscular Diseases, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, London WC1N 3BG, United Kingdom; and eDepartment of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, United Kingdom Edited by Douglas Koshland, University of California, Berkeley, CA, and approved June 7, 2016 (received for review January 18, 2016) The genetic information in mammalian mitochondrial DNA is densely Results packed; there are no introns and only one sizeable noncoding, or Analysis of RNA hybridized to mtDNA must contend with the control, region containing key cis-elements for its replication and ready degradation of the RNA during extraction (16). Previous expression. Many molecules of mitochondrial DNA bear a third analysis of fragments of mtDNA encompassing the CR dem- strand of DNA, known as “7S DNA,” which forms a displacement onstrated that they included molecules with 7S DNA, as (D-) loop in the control region.
    [Show full text]
  • Characterizing Genomic Duplication in Autism Spectrum Disorder by Edward James Higginbotham a Thesis Submitted in Conformity
    Characterizing Genomic Duplication in Autism Spectrum Disorder by Edward James Higginbotham A thesis submitted in conformity with the requirements for the degree of Master of Science Graduate Department of Molecular Genetics University of Toronto © Copyright by Edward James Higginbotham 2020 i Abstract Characterizing Genomic Duplication in Autism Spectrum Disorder Edward James Higginbotham Master of Science Graduate Department of Molecular Genetics University of Toronto 2020 Duplication, the gain of additional copies of genomic material relative to its ancestral diploid state is yet to achieve full appreciation for its role in human traits and disease. Challenges include accurately genotyping, annotating, and characterizing the properties of duplications, and resolving duplication mechanisms. Whole genome sequencing, in principle, should enable accurate detection of duplications in a single experiment. This thesis makes use of the technology to catalogue disease relevant duplications in the genomes of 2,739 individuals with Autism Spectrum Disorder (ASD) who enrolled in the Autism Speaks MSSNG Project. Fine-mapping the breakpoint junctions of 259 ASD-relevant duplications identified 34 (13.1%) variants with complex genomic structures as well as tandem (193/259, 74.5%) and NAHR- mediated (6/259, 2.3%) duplications. As whole genome sequencing-based studies expand in scale and reach, a continued focus on generating high-quality, standardized duplication data will be prerequisite to addressing their associated biological mechanisms. ii Acknowledgements I thank Dr. Stephen Scherer for his leadership par excellence, his generosity, and for giving me a chance. I am grateful for his investment and the opportunities afforded me, from which I have learned and benefited. I would next thank Drs.
    [Show full text]
  • Structure of the Essential MTERF4:NSUN4 Protein Complex Reveals How an MTERF Protein Collaborates to Facilitate Rrna Modification
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Structure Article Structure of the Essential MTERF4:NSUN4 Protein Complex Reveals How an MTERF Protein Collaborates to Facilitate rRNA Modification Elena Yakubovskaya,1,2 Kip E. Guja,1,2 Edison Mejia,1,2 Steven Castano,1 Elena Hambardjieva,1 Woo Suk Choi,1 and Miguel Garcia-Diaz1,* 1Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794, USA 2These authors contributed equally to this work *Correspondence: [email protected] http://dx.doi.org/10.1016/j.str.2012.08.027 SUMMARY nizes a sequence in the mitochondrial tRNA-Leu(UUR) gene, which is downstream and adjacent to the 16S rRNA gene MTERF4 is the first MTERF family member shown to and promotes bidirectional transcriptional termination (Asin- bind RNA and plays an essential role as a regulator of Cayuela et al., 2005; Yakubovskaya et al., 2010). MTERF2 and ribosomal biogenesis in mammalian mitochondria. It MTERF3 have been proposed to associate with mitochondrial forms a complex with the rRNA methyltransferase DNA in a nonsequence-specific manner and regulate mtDNA NSUN4 and recruits it to the large ribosomal subunit. transcription (Park et al., 2007; Roberti et al., 2009; Wenz In this article, we characterize the interaction et al., 2009). Recently, crystal structures of MTERF1 (Jime´ nez-Mene´ ndez between both proteins, demonstrate that MTERF4 et al., 2010; Yakubovskaya et al., 2010) and MTERF3 (Spa˚ hr strongly stimulates the specificity of NSUN4 during et al., 2010) have revealed that these proteins share a unique in vitro methylation experiments, and present the superhelical fold.
    [Show full text]
  • Regulation and Retrograde Coordination of Mitochondrial Gene Expression Adnan Khan Niazi
    Regulation and retrograde coordination of mitochondrial gene expression Adnan Khan Niazi To cite this version: Adnan Khan Niazi. Regulation and retrograde coordination of mitochondrial gene expression. Agri- cultural sciences. Université de Strasbourg, 2013. English. NNT : 2013STRAJ026. tel-00940588 HAL Id: tel-00940588 https://tel.archives-ouvertes.fr/tel-00940588 Submitted on 2 Feb 2014 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. UNIVERSITE DE STRASBOURG THESE DE DOCTORAT Présentée à la FACULTE DES SCIENCES DE LA VIE En vue de l’obtention du titre de DOCTEUR DE L’UNIVERSITE DE STRASBOURG Spécialité : Aspects Moléculaires et Cellulaires de la Biologie Par Adnan Khan NIAZI Régulation et coordination rétrograde de l'expression génétique mitochondriale Regulation and retrograde coordination of mitochondrial gene expression Soutenue le 26 Juin 2013 devant le jury composé de Pr. David MACHEREL (Université d'Angers) Rapporteur externe Pr. Mizuki TAKENAKA (Université de Ulm) Rapporteur externe Dr. Pascale ROMBY (CNRS - Université de Strasbourg) Examinateur Dr. André DIETRICH (CNRS - Université de Strasbourg) Directeur de thèse Membre invité : Frédérique WEBER-LOTFI (Université de Strasbourg) Unité de Recherche Institut de Biologie Moléculaire des Plantes - CNRS UPR2357 Strasbourg, FRANCE Acknowledgements I humbly bow my head before ALLAH, the most beneficent and merciful, whose blessing flourished my thoughts and thrived my ambitions.
    [Show full text]
  • Mitochondrial Mrna Translation Is Required for Maintenance of Oxidative Capacity David Lee University of Arkansas, Fayetteville
    University of Arkansas, Fayetteville ScholarWorks@UARK Theses and Dissertations 5-2018 Mitochondrial mRNA Translation is Required for Maintenance of Oxidative Capacity David Lee University of Arkansas, Fayetteville Follow this and additional works at: http://scholarworks.uark.edu/etd Part of the Cell Biology Commons, Molecular Biology Commons, and the Molecular, Cellular, and Tissue Engineering Commons Recommended Citation Lee, David, "Mitochondrial mRNA Translation is Required for Maintenance of Oxidative Capacity" (2018). Theses and Dissertations. 2626. http://scholarworks.uark.edu/etd/2626 This Dissertation is brought to you for free and open access by ScholarWorks@UARK. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of ScholarWorks@UARK. For more information, please contact [email protected], [email protected]. Mitochondrial mRNA Translation is Required for Maintenance of Oxidative Capacity A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Kinesiology David E. Lee Louisiana State University – Shreveport Bachelor of Science in Kinesiology, 2012 University of Arkansas Master of Science in Kinesiology, 2015 May 2018 University of Arkansas This dissertation is approved for recommendation to the Graduate Council. ________________________________ Nicholas P. Greene, Ph.D. Dissertation Committee Chair ________________________________ ______________________________ Tyrone A. Washington, Ph.D. Narasimhan Rajaram, Ph.D. Committee Member
    [Show full text]
  • Functional and Comparative Genomics Reveals Conserved Noncoding Sequences In
    bioRxiv preprint doi: https://doi.org/10.1101/2021.07.27.453985; this version posted July 29, 2021. 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 Functional and comparative genomics reveals conserved noncoding sequences in 2 the nitrogen-fixing clade 3 4 Running title: Sequence conservation in the nitrogen-fixing clade 5 6 Wendell J. Pereira1, Sara Knaack2, Daniel Conde1, Sanhita Chakraborty3, Ryan A. Folk4, Paolo 7 M. Triozzi1, Kelly M. Balmant1, Christopher Dervinis1, Henry W. Schmidt1, Jean-Michel Ané3,5, 8 Sushmita Roy2, Matias Kirst1,6*. 9 10 1 School of Forest, Fisheries and Geomatics Sciences, University of Florida, Gainesville, FL 11 32611, USA. 12 2 Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, 13 Madison, WI 53715, USA. 14 3 Department of Bacteriology, University of Wisconsin-Madison, Madison, WI 53706, USA. 15 4 Department of Biological Sciences, Mississippi State University, Starkville, MS 39762, USA. 16 5 Department of Agronomy, University of Wisconsin-Madison, Madison, WI 53706, USA. 17 6 Genetics Institute, University of Florida, Gainesville, FL 32611, USA. 18 19 *Correspondent author: [email protected] 20 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.07.27.453985; this version posted July 29, 2021. 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. 21 ABSTRACT 22 Nitrogen is one of the most inaccessible plant nutrients, but certain species have overcome this 23 limitation by establishing symbiotic interactions with nitrogen-fixing bacteria in the root nodule.
    [Show full text]
  • The Changing Chromatome As a Driver of Disease: a Panoramic View from Different Methodologies
    The changing chromatome as a driver of disease: A panoramic view from different methodologies Isabel Espejo1, Luciano Di Croce,1,2,3 and Sergi Aranda1 1. Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain 2. Universitat Pompeu Fabra (UPF), Barcelona, Spain 3. ICREA, Pg. Lluis Companys 23, Barcelona 08010, Spain *Corresponding authors: Luciano Di Croce ([email protected]) Sergi Aranda ([email protected]) 1 GRAPHICAL ABSTRACT Chromatin-bound proteins regulate gene expression, replicate and repair DNA, and transmit epigenetic information. Several human diseases are highly influenced by alterations in the chromatin- bound proteome. Thus, biochemical approaches for the systematic characterization of the chromatome could contribute to identifying new regulators of cellular functionality, including those that are relevant to human disorders. 2 SUMMARY Chromatin-bound proteins underlie several fundamental cellular functions, such as control of gene expression and the faithful transmission of genetic and epigenetic information. Components of the chromatin proteome (the “chromatome”) are essential in human life, and mutations in chromatin-bound proteins are frequently drivers of human diseases, such as cancer. Proteomic characterization of chromatin and de novo identification of chromatin interactors could thus reveal important and perhaps unexpected players implicated in human physiology and disease. Recently, intensive research efforts have focused on developing strategies to characterize the chromatome composition. In this review, we provide an overview of the dynamic composition of the chromatome, highlight the importance of its alterations as a driving force in human disease (and particularly in cancer), and discuss the different approaches to systematically characterize the chromatin-bound proteome in a global manner.
    [Show full text]
  • Content Based Search in Gene Expression Databases and a Meta-Analysis of Host Responses to Infection
    Content Based Search in Gene Expression Databases and a Meta-analysis of Host Responses to Infection A Thesis Submitted to the Faculty of Drexel University by Francis X. Bell in partial fulfillment of the requirements for the degree of Doctor of Philosophy November 2015 c Copyright 2015 Francis X. Bell. All Rights Reserved. ii Acknowledgments I would like to acknowledge and thank my advisor, Dr. Ahmet Sacan. Without his advice, support, and patience I would not have been able to accomplish all that I have. I would also like to thank my committee members and the Biomed Faculty that have guided me. I would like to give a special thanks for the members of the bioinformatics lab, in particular the members of the Sacan lab: Rehman Qureshi, Daisy Heng Yang, April Chunyu Zhao, and Yiqian Zhou. Thank you for creating a pleasant and friendly environment in the lab. I give the members of my family my sincerest gratitude for all that they have done for me. I cannot begin to repay my parents for their sacrifices. I am eternally grateful for everything they have done. The support of my sisters and their encouragement gave me the strength to persevere to the end. iii Table of Contents LIST OF TABLES.......................................................................... vii LIST OF FIGURES ........................................................................ xiv ABSTRACT ................................................................................ xvii 1. A BRIEF INTRODUCTION TO GENE EXPRESSION............................. 1 1.1 Central Dogma of Molecular Biology........................................... 1 1.1.1 Basic Transfers .......................................................... 1 1.1.2 Uncommon Transfers ................................................... 3 1.2 Gene Expression ................................................................. 4 1.2.1 Estimating Gene Expression ............................................ 4 1.2.2 DNA Microarrays ......................................................
    [Show full text]
  • Epigenetic Regulation of Mitochondrial Quality Control Genes in Multiple Myeloma: a Sequenom Massarray Pilot Investigation on Hmcls
    Journal of Clinical Medicine Communication Epigenetic Regulation of Mitochondrial Quality Control Genes in Multiple Myeloma: A Sequenom MassARRAY Pilot Investigation on HMCLs Patrizia D’Aquila 1,†, Domenica Ronchetti 2,3,† , Maria Eugenia Gallo Cantafio 4, Katia Todoerti 2,3, Elisa Taiana 2,3 , Fernanda Fabiani 5, Alberto Montesanto 1, Antonino Neri 2,3, Giuseppe Passarino 1 , Giuseppe Viglietto 4, Dina Bellizzi 1,‡ and Nicola Amodio 4,*,‡ 1 Department of Cell Biology, Ecology and Earth Sciences, University of Calabria, 87036 Rende, Italy; [email protected] (P.D.); [email protected] (A.M.); [email protected] (G.P.); [email protected] (D.B.) 2 Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy; [email protected] (D.R.); [email protected] (K.T.); [email protected] (E.T.); [email protected] (A.N.) 3 Hematology, Fondazione Cà Granda IRCCS Policlinico, 20122 Milan, Italy 4 Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; [email protected] (M.E.G.C.); [email protected] (G.V.) 5 Medical Genetics, University “Magna Graecia”, 88100 Catanzaro, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-0961-3694159 † P.D. and D.R. equally contributed to this work. ‡ D.B. and N.A. equally contributed to this work. Citation: D’Aquila, P.; Ronchetti, D.; Gallo Cantafio, M.E.; Todoerti, K.; Abstract: The mitochondrial quality control network includes several epigenetically-regulated genes Taiana, E.; Fabiani, F.; Montesanto, A.; involved in mitochondrial dynamics, mitophagy, and mitochondrial biogenesis under physiologic Neri, A.; Passarino, G.; Viglietto, G.; conditions.
    [Show full text]