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      PNPase knockout results in mtDNA loss and an altered metabolic gene expression program

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          Abstract

          Polynucleotide phosphorylase (PNPase) is an essential mitochondria-localized exoribonuclease implicated in multiple biological processes and human disorders. To reveal role(s) for PNPase in mitochondria, we established PNPase knockout (PKO) systems by first shifting culture conditions to enable cell growth with defective respiration. Interestingly, PKO established in mouse embryonic fibroblasts (MEFs) resulted in the loss of mitochondrial DNA (mtDNA). The transcriptional profile of PKO cells was similar to rho 0 mtDNA deleted cells, with perturbations in cholesterol (FDR = 6.35 x 10 −13), lipid (FDR = 3.21 x 10 −11), and secondary alcohol (FDR = 1.04x10 -12) metabolic pathway gene expression compared to wild type parental (TM6) MEFs. Transcriptome analysis indicates processes related to axonogenesis (FDR = 4.49 x 10 −3), axon development (FDR = 4.74 x 10 −3), and axonal guidance (FDR = 4.74 x 10 −3) were overrepresented in PKO cells, consistent with previous studies detailing causative PNPase mutations in delayed myelination, hearing loss, encephalomyopathy, and chorioretinal defects in humans. Overrepresentation analysis revealed alterations in metabolic pathways in both PKO and rho 0 cells. Therefore, we assessed the correlation of genes implicated in cell cycle progression and total metabolism and observed a strong positive correlation between PKO cells and rho 0 MEFs compared to TM6 MEFs. We quantified the normalized biomass accumulation rate of PKO clones at 1.7% (SD ± 2.0%) and 2.4% (SD ± 1.6%) per hour, which was lower than TM6 cells at 3.3% (SD ± 3.5%) per hour. Furthermore, PKO in mouse inner ear hair cells caused progressive hearing loss that parallels human familial hearing loss previously linked to mutations in PNPase. Combined, our study reports that knockout of a mitochondrial nuclease results in mtDNA loss and suggests that mtDNA maintenance could provide a unifying connection for the large number of biological activities reported for PNPase.

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          Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

          Yoav Benjamini, Yosef Hochberg (1995)
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            Rank–rank hypergeometric overlap: identification of statistically significant overlap between gene-expression signatures

            Seema B. Plaisier, Richard Taschereau, Justin A. Wong … (2010)
            Comparing independent high-throughput gene-expression experiments can generate hypotheses about which gene-expression programs are shared between particular biological processes. Current techniques to compare expression profiles typically involve choosing a fixed differential expression threshold to summarize results, potentially reducing sensitivity to small but concordant changes. We present a threshold-free algorithm called Rank–rank Hypergeometric Overlap (RRHO). This algorithm steps through two gene lists ranked by the degree of differential expression observed in two profiling experiments, successively measuring the statistical significance of the number of overlapping genes. The output is a graphical map that shows the strength, pattern and bounds of correlation between two expression profiles. To demonstrate RRHO sensitivity and dynamic range, we identified shared expression networks in cancer microarray profiles driving tumor progression, stem cell properties and response to targeted kinase inhibition. We demonstrate how RRHO can be used to determine which model system or drug treatment best reflects a particular biological or disease response. The threshold-free and graphical aspects of RRHO complement other rank-based approaches such as Gene Set Enrichment Analysis (GSEA), for which RRHO is a 2D analog. Rank–rank overlap analysis is a sensitive, robust and web-accessible method for detecting and visualizing overlap trends between two complete, continuous gene-expression profiles. A web-based implementation of RRHO can be accessed at http://systems.crump.ucla.edu/rankrank/ .
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              Smaller inner ear sensory epithelia in Neurog 1 null mice are related to earlier hair cell cycle exit.

              V. Matei, S Pauley, S Kaing … (2005)
              We investigated whether co-expression of Neurog 1 and Atoh 1 in common neurosensory precursors could explain the loss of hair cells in Neurog 1 null mice. Analysis of terminal mitosis, using BrdU, supports previous findings regarding timing of exit from cell cycle. Specifically, we show that cell cycle exit occurs in spiral sensory neurons in a base-to-apex progression followed by cell cycle exit of hair cells in the organ of Corti in an apex-to-base progression, with some overlap of cell cycle exit in the apex for both hair cells and spiral sensory neurons. Hair cells in Neurog 1 null mice show cell cycle exit in an apex-to-base progression about 1-2 days earlier. Atoh 1 is expressed in an apex-to-base progression rather then a base-to-apex progression as in wildtype littermates. We tested the possible expression of Atoh1 in neurosensory precursors using two Atoh 1-Cre lines. We show Atoh 1-Cre mediated beta-galactosidase expression in delaminating sensory neuron precursors as well as undifferentiated epithelial cells at E11 and E12.5. PCR analysis shows expression of Atoh 1 in the otocyst as early as E10.5, prior to any histology-based detection techniques. Combined, these data suggest that low levels of Atoh 1 exist much earlier in precursors of hair cells and sensory neurons, possibly including neurosensory precursors. Analysis of Atoh 1-Cre expression in E18.5 embryos and P31 mice reveal beta-galactosidase stain in all hair cells but also in vestibular and cochlear sensory neurons and some supporting cells. A similar expression of Atoh 1-LacZ exists in postnatal and adult vestibular and cochlear sensory neurons, and Atoh 1 expression in vestibular sensory neurons is confirmed with RT-PCR. We propose that the absence of NEUROG 1 protein leads to loss of sensory neuron formation through a phenotypic switch of cycling neurosensory precursors from sensory neuron to hair cell fate. Neurog 1 null mice show a truncation of clonal expansion of hair cell precursors through temporally altered terminal mitosis, thereby resulting in smaller sensory epithelia. Developmental Dynamics 234:633-650, 2005. (c) 2005 Wiley-Liss, Inc.
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                Author and article information

                Contributors
                Eriko Shimada: Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Writing – original draftRole: Writing – review & editing
                Fasih M. Ahsan: Role: InvestigationRole: MethodologyRole: Writing – original draft
                Mahta Nili: Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Writing – review & editing
                Dian Huang: Role: InvestigationRole: Writing – review & editing
                Sean Atamdede: Role: Investigation
                Tara TeSlaa: Role: InvestigationRole: Writing – review & editing
                Dana Case: Role: InvestigationRole: Writing – review & editing
                Xiang Yu: Role: Writing – review & editing
                Brian D. Gregory: Role: Conceptualization
                Benjamin J. Perrin: Role: InvestigationRole: Resources
                Carla M. Koehler: Role: ConceptualizationRole: Funding acquisitionRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Michael A. Teitell:
                ORCID: http://orcid.org/0000-0002-4495-8750
                Role: ConceptualizationRole: Funding acquisitionRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Maria Moran: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 19 July 2018
                Publication date Collection: 2018
                Volume: 13
                Issue: 7
                Electronic Location Identifier: e0200925
                Affiliations
                [1 ] Molecular Biology Institute Interdepartmental Program, University of California Los Angeles, Los Angeles, California, United States of America
                [2 ] Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California, United States of America
                [3 ] Department of Bioengineering, University of California Los Angeles, Los Angeles, California, United States of America
                [4 ] Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, California, United States of America
                [5 ] Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
                [6 ] Department of Biology, Indiana University–Purdue University Indianapolis, Indianapolis, Indiana, United States of America
                [7 ] Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, California, United States of America
                [8 ] Broad Center for Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, California, United States of America
                [9 ] Department of Pediatrics, University of California Los Angeles, Los Angeles, California, United States of America
                [10 ] California NanoSystems Institute, University of California Los Angeles, Los Angeles, California, United States of America
                Instituto de Investigacion Hospital 12 de Octubre, SPAIN
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-4495-8750
                Article
                Publisher ID: PONE-D-18-01754
                DOI: 10.1371/journal.pone.0200925
                PMC ID: 6053217
                PubMed ID: 30024931
                SO-VID: 92e77be3-3534-438b-b141-f5ac8b4392c5
                Copyright © © 2018 Shimada et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 17 January 2018
                Date accepted : 5 July 2018
                Page count
                Figures: 4, Tables: 0, Pages: 22
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: GM073981
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: GM114188
                Award Recipient :
                ORCID: http://orcid.org/0000-0002-4495-8750
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: CA185189
                Award Recipient :
                ORCID: http://orcid.org/0000-0002-4495-8750
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: GM61721
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000900, California Institute for Regenerative Medicine;
                Award ID: RT307678
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: NS076228
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000181, Air Force Office of Scientific Research;
                Award ID: FA9550-15-1-0406
                Award Recipient :
                ORCID: http://orcid.org/0000-0002-4495-8750
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: CA009120
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: GM007185
                Award Recipient :
                This work was supported by National Institutes of Health awards CA90571 (MAT), CA156674 (MAT), GM073981 (MAT and CMK), GM114188 (MAT), CA185189 (MAT), and GM61721 (CMK); California Institute of Regenerative Medicine RT307678 (CMK and MAT); National Institutes of Health Ruth L. Kirschstein National Research Service Award NS076228 (ES); Whitcome Pre-doctoral Training Program (UCLA) (ES); and an MBI-IDP Special Award (UCLA) (ES). Air Force Office of Scientific Research FA9550-15-1-0406, National Institutes of Health CA009120, National Institutes of Health GM007185. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology and life sciences
                Subject: Genetics
                Subject: DNA
                Subject: Forms of DNA
                Subject: Mitochondrial DNA
                Subject: Biology and life sciences
                Subject: Biochemistry
                Subject: Nucleic acids
                Subject: DNA
                Subject: Forms of DNA
                Subject: Mitochondrial DNA
                Subject: Biology and Life Sciences
                Subject: Genetics
                Subject: Gene Expression
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Bioenergetics
                Subject: Energy-Producing Organelles
                Subject: Mitochondria
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cellular Structures and Organelles
                Subject: Energy-Producing Organelles
                Subject: Mitochondria
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cell Processes
                Subject: Cell Cycle and Cell Division
                Subject: Medicine and Health Sciences
                Subject: Otorhinolaryngology
                Subject: Otology
                Subject: Hearing Disorders
                Subject: Deafness
                Subject: Biology and Life Sciences
                Subject: Molecular Biology
                Subject: Molecular Biology Techniques
                Subject: Cloning
                Subject: Research and Analysis Methods
                Subject: Molecular Biology Techniques
                Subject: Cloning
                Subject: Biology and Life Sciences
                Subject: Computational Biology
                Subject: Genome Analysis
                Subject: Gene Ontologies
                Subject: Biology and Life Sciences
                Subject: Genetics
                Subject: Genomics
                Subject: Genome Analysis
                Subject: Gene Ontologies
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cell Processes
                Subject: Cell Growth
                Custom metadata
                Data Availability All raw RNA-Seq reads and processed gene count matrices are in submission to the NCBI Short Read Archive (SRA) and Gene Expression Omnibus (GEO), respectively. GEO accession number: GSE111668.

                ScienceOpen disciplines: Uncategorized
                Data availability:
                ScienceOpen disciplines: Uncategorized

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