ERBB2 Drives YAP Activation and EMT-Like Processes During Cardiac Regeneration
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Transcriptome and DNA Methylation Analyses of the Molecular Mechanisms Underlying with Longissimus Dorsi Muscles at Different Stages of Development in the Polled Yak
G C A T T A C G G C A T genes Article Transcriptome and DNA Methylation Analyses of the Molecular Mechanisms Underlying with Longissimus dorsi Muscles at Different Stages of Development in the Polled Yak Xiaoming Ma 1,2, Congjun Jia 1,2, Min Chu 1,2, Donghai Fu 1,2 , Qinhui Lei 1,2, Xuezhi Ding 1,2, Xiaoyun Wu 1,2, Xian Guo 1,2, Jie Pei 1,2, Pengjia Bao 1,2, Ping Yan 1,* and Chunnian Liang 2,* 1 Animal Science Department, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou 730050, China; [email protected] (X.M.); [email protected] (C.J.); [email protected] (M.C.); [email protected] (D.F.); [email protected] (Q.L.); [email protected] (X.D.); [email protected] (X.W.); [email protected] (X.G.); [email protected] (J.P.); [email protected] (P.B.) 2 Key Laboratory for Yak Genetics, Breeding, and Reproduction Engineering of Gansu Province, Chinese Academy of Agricultural Sciences, Lanzhou 730050, China * Correspondence: [email protected] (P.Y.); [email protected] (C.L.); Tel.: +86-0931-2115288 (P.Y.); +86-0931-2115271 (C.L.) Received: 29 October 2019; Accepted: 21 November 2019; Published: 26 November 2019 Abstract: DNA methylation modifications are implicated in many biological processes. As the most common epigenetic mechanism DNA methylation also affects muscle growth and development. The majority of previous studies have focused on different varieties of yak, but little is known about the epigenetic regulation mechanisms in different age groups of animals. -
Gene Expression During Normal and FSHD Myogenesis Tsumagari Et Al
Gene expression during normal and FSHD myogenesis Tsumagari et al. Tsumagari et al. BMC Medical Genomics 2011, 4:67 http://www.biomedcentral.com/1755-8794/4/67 (27 September 2011) Tsumagari et al. BMC Medical Genomics 2011, 4:67 http://www.biomedcentral.com/1755-8794/4/67 RESEARCHARTICLE Open Access Gene expression during normal and FSHD myogenesis Koji Tsumagari1, Shao-Chi Chang1, Michelle Lacey2,3, Carl Baribault2,3, Sridar V Chittur4, Janet Sowden5, Rabi Tawil5, Gregory E Crawford6 and Melanie Ehrlich1,3* Abstract Background: Facioscapulohumeral muscular dystrophy (FSHD) is a dominant disease linked to contraction of an array of tandem 3.3-kb repeats (D4Z4) at 4q35. Within each repeat unit is a gene, DUX4, that can encode a protein containing two homeodomains. A DUX4 transcript derived from the last repeat unit in a contracted array is associated with pathogenesis but it is unclear how. Methods: Using exon-based microarrays, the expression profiles of myogenic precursor cells were determined. Both undifferentiated myoblasts and myoblasts differentiated to myotubes derived from FSHD patients and controls were studied after immunocytochemical verification of the quality of the cultures. To further our understanding of FSHD and normal myogenesis, the expression profiles obtained were compared to those of 19 non-muscle cell types analyzed by identical methods. Results: Many of the ~17,000 examined genes were differentially expressed (> 2-fold, p < 0.01) in control myoblasts or myotubes vs. non-muscle cells (2185 and 3006, respectively) or in FSHD vs. control myoblasts or myotubes (295 and 797, respectively). Surprisingly, despite the morphologically normal differentiation of FSHD myoblasts to myotubes, most of the disease-related dysregulation was seen as dampening of normal myogenesis- specific expression changes, including in genes for muscle structure, mitochondrial function, stress responses, and signal transduction. -
IDENTIFICATION and CHARACTERIZATION of ACTIN-REGULATORY PROTEINS in the HAIR CELL's CUTICULAR PLATE by LANA MARY POLLOCK Subm
IDENTIFICATION AND CHARACTERIZATION OF ACTIN-REGULATORY PROTEINS IN THE HAIR CELL’S CUTICULAR PLATE by LANA MARY POLLOCK Submitted in partial fulfilment of the requirements for the degree of Doctor of Philosophy Dissertation advisor: Brian M. McDermott Jr., Ph.D. Department of Genetics and Genome Sciences CASE WESTERN RESERVE UNIVERSITY January 2016 Case Western Reserve University School of Graduate Studies We, the thesis committee, hereby approve the thesis/dissertation of Lana Pollock, candidate for the degree of Doctor of Philosophy (PhD).* (signed)_________Zhenghe Wang, Ph.D._________________ (chair of committee) ___________Brian McDermott, Ph.D._______________ ___________ Hua Lou, Ph.D._____________________ ___________Stephen Maricich, Ph.D., M.D.___________ ___________Anthony Wynshaw-Boris, Ph.D., M.D._____ Date of defense_____September 8th, 2015_______________ *we also certify that written approval has been obtained for release of any proprietary material contained therein 2 This thesis is dedicated to Daniel Margevicius. Thank you for your unwavering love and support. Ačiū!! 3 Table of contents List of Tables ........................................................................................................ 7 List of Figures ....................................................................................................... 8 List of abbreviations ............................................................................................ 13 Abstract ............................................................................................................. -
Molecular Profiling and Sequential Somatic Mutation Shift In
www.nature.com/scientificreports OPEN Molecular profling and sequential somatic mutation shift in hypermutator tumours harbouring Received: 4 October 2017 Accepted: 23 May 2018 POLE mutations Published: xx xx xxxx Keiichi Hatakeyama1, Keiichi Ohshima1, Takeshi Nagashima2,3, Shumpei Ohnami2, Sumiko Ohnami2, Masakuni Serizawa4, Yuji Shimoda2,3, Koji Maruyama5, Yasuto Akiyama6, Kenichi Urakami2, Masatoshi Kusuhara7,4, Tohru Mochizuki1 & Ken Yamaguchi8 Defective DNA polymerase ε (POLE) proofreading leads to extensive somatic mutations that exhibit biased mutational properties; however, the characteristics of POLE-mutated tumours remain unclear. In the present study, we describe a molecular profle using whole exome sequencing based on the transition of somatic mutations in 10 POLE-mutated solid tumours that were obtained from 2,042 Japanese patients. The bias of accumulated variations in these mutants was quantifed to follow a pattern of somatic mutations, thereby classifying the sequential mutation shift into three periods. During the period prior to occurrence of the aberrant POLE, bare accumulation of mutations in cancer- related genes was observed, whereas PTEN was highly mutated in conjunction with or subsequent to the event, suggesting that POLE and PTEN mutations were responsible for the development of POLE- mutated tumours. Furthermore, homologous recombination was restored following the occurrence of PTEN mutations. Our strategy for estimation of the footprint of somatic mutations may provide new insight towards the understanding of mutation-driven tumourigenesis. Large-scale genomic studies have revealed the rare occurrence of a diversity of mutation frequency and somatic hypermutation in specifc tumours, which are termed ‘hypermutators’1–3. Tis mutator efect in colorectal and endometrial cancers is occasionally accompanied by mutations in the exonuclease domain of DNA polymerase epsilon (POLE)2–4. -
S41419-021-03972-6.Pdf
www.nature.com/cddis ARTICLE OPEN Primed to die: an investigation of the genetic mechanisms underlying noise-induced hearing loss and cochlear damage in homozygous Foxo3-knockout mice ✉ Holly J. Beaulac1,3, Felicia Gilels1,4, Jingyuan Zhang1,5, Sarah Jeoung2 and Patricia M. White 1 © The Author(s) 2021 The prevalence of noise-induced hearing loss (NIHL) continues to increase, with limited therapies available for individuals with cochlear damage. We have previously established that the transcription factor FOXO3 is necessary to preserve outer hair cells (OHCs) and hearing thresholds up to two weeks following mild noise exposure in mice. The mechanisms by which FOXO3 preserves cochlear cells and function are unknown. In this study, we analyzed the immediate effects of mild noise exposure on wild-type, Foxo3 heterozygous (Foxo3+/−), and Foxo3 knock-out (Foxo3−/−) mice to better understand FOXO3’s role(s) in the mammalian cochlea. We used confocal and multiphoton microscopy to examine well-characterized components of noise-induced damage including calcium regulators, oxidative stress, necrosis, and caspase-dependent and caspase-independent apoptosis. Lower immunoreactivity of the calcium buffer Oncomodulin in Foxo3−/− OHCs correlated with cell loss beginning 4 h post-noise exposure. Using immunohistochemistry, we identified parthanatos as the cell death pathway for OHCs. Oxidative stress response pathways were not significantly altered in FOXO3’s absence. We used RNA sequencing to identify and RT-qPCR to confirm differentially expressed genes. We further investigated a gene downregulated in the unexposed Foxo3−/− mice that may contribute to OHC noise susceptibility. Glycerophosphodiester phosphodiesterase domain containing 3 (GDPD3), a possible endogenous source of lysophosphatidic acid (LPA), has not previously been described in the cochlea. -
The Use of Genetic Analyses and Functional Assays for the Interpretation of Rare Variants in Pediatric Heart Disease
The use of genetic analyses and functional assays for the interpretation of rare variants in pediatric heart disease A dissertation submitted to the Division of Graduate Studies and Research, University of Cincinnati in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Molecular Genetics by Jeffrey A. Schubert Bachelor of Science, Mount St. Joseph University, 2012 Committee Chair: Stephanie M. Ware, M.D., Ph.D. Edmund Choi, Ph.D. Benjamin Landis, M.D. Anil Menon, Ph.D. David Wieczorek, Ph.D. Molecular Genetics, Biochemistry, and Microbiology Graduate Program College of Medicine, University of Cincinnati Cincinnati, Ohio, USA, 2018 ABSTRACT The use of next generation technologies such as whole exome sequencing (WES) has paved the way for discovering novel causes of Mendelian diseases. This has been demonstrated in pediatric heart diseases, including cardiomyopathy (CM) and familial thoracic aortic aneurysm (TAA). Each of these conditions carries a high risk of a serious cardiac event, including sudden heart failure or aortic rupture, which are often fatal. Patients with either disease can be asymptomatic before presenting with these events, which necessitates early diagnosis. Though there are many known genetic causes of disease for both conditions, there is still room for discovery of novel pathogenic genes and variants, as many patients have an undefined genetic diagnosis. WES covers the protein-coding portion of the genome, which yields a massive amount of data, though it comprises only 1% of the genome. Sorting and filtering sequencing information to identify (sometimes) a single base pair change responsible for the patient phenotype is challenging. Further, interpreting identified candidate variants must be done according to strict standards, which makes it difficult to definitively say whether a coding change is pathogenic or benign. -
Structure and Function of Filamin C in the Muscle Z-Disc
International Journal of Molecular Sciences Review Structure and Function of Filamin C in the Muscle Z-Disc Zhenfeng Mao and Fumihiko Nakamura * School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China; [email protected] * Correspondence: [email protected] Received: 17 March 2020; Accepted: 9 April 2020; Published: 13 April 2020 Abstract: Filamin C (FLNC) is one of three filamin proteins (Filamin A (FLNA), Filamin B (FLNB), and FLNC) that cross-link actin filaments and interact with numerous binding partners. FLNC consists of a N-terminal actin-binding domain followed by 24 immunoglobulin-like repeats with two intervening calpain-sensitive hinges separating R15 and R16 (hinge 1) and R23 and R24 (hinge-2). The FLNC subunit is dimerized through R24 and calpain cleaves off the dimerization domain to regulate mobility of the FLNC subunit. FLNC is localized in the Z-disc due to the unique insertion of 82 amino acid residues in repeat 20 and necessary for normal Z-disc formation that connect sarcomeres. Since phosphorylation of FLNC by PKC diminishes the calpain sensitivity, assembly, and disassembly of the Z-disc may be regulated by phosphorylation of FLNC. Mutations of FLNC result in cardiomyopathy and muscle weakness. Although this review will focus on the current understanding of FLNC structure and functions in muscle, we will also discuss other filamins because they share high sequence similarity and are better characterized. We will also discuss a possible role of FLNC as a mechanosensor during muscle contraction. Keywords: Filamin C; FLNC; sarcomere; Z-disc; mutation; filaminopathy; myopathy 1. Introduction Filamin C (FLNC) protein is one of three filamin isoforms (A, B, C) that cross-link actin filaments (F-actin) and interact with various binding partners [1,2]. -
Genetic and Epigenetic Studies of Atopic Dermatitis Lianghua Bin1,2,3 and Donald Y
Bin and Leung Allergy Asthma Clin Immunol (2016) 12:52 Allergy, Asthma & Clinical Immunology DOI 10.1186/s13223-016-0158-5 REVIEW Open Access Genetic and epigenetic studies of atopic dermatitis Lianghua Bin1,2,3 and Donald Y. M. Leung3,4* Abstract Background: Atopic dermatitis (AD) is a chronic inflammatory disease caused by the complex interaction of genetic, immune and environmental factors. There have many recent discoveries involving the genetic and epigenetic studies of AD. Methods: A retrospective PubMed search was carried out from June 2009 to June 2016 using the terms “atopic dermatitis”, “association”, “eczema”, “gene”, “polymorphism”, “mutation”, “variant”, “genome wide association study”, “micro- array” “gene profiling”, “RNA sequencing”, “epigenetics” and “microRNA”. A total of 132 publications in English were identified. Results: To elucidate the genetic factors for AD pathogenesis, candidate gene association studies, genome-wide association studies (GWAS) and transcriptomic profiling assays have been performed in this period. Epigenetic mecha- nisms for AD development, including genomic DNA modification and microRNA posttranscriptional regulation, have been explored. To date, candidate gene association studies indicate that filaggrin (FLG) null gene mutations are the most significant known risk factor for AD, and genes in the type 2 T helper lymphocyte (Th2) signaling pathways are the second replicated genetic risk factor for AD. GWAS studies identified 34 risk loci for AD, these loci also suggest that genes in immune responses and epidermal skin barrier functions are associated with AD. Additionally, gene profiling assays demonstrated AD is associated with decreased gene expression of epidermal differentiation complex genes and elevated Th2 and Th17 genes. Hypomethylation of TSLP and FCER1G in AD were reported; and miR-155, which target the immune suppressor CTLA-4, was found to be significantly over-expressed in infiltrating T cells in AD skin lesions. -
Identification of Xin-Repeat Proteins As Novel Ligands Of
M BoC | ARTICLE Identification of Xin-repeat proteins as novel ligands of the SH3 domains of nebulin and nebulette and analysis of their interaction during myofibril formation and remodeling Stefan Eulitza, Florian Sauerb,*, Marie-Cecile Pelissierb, Prisca Boisguerinc,†, Sibylle Molta, Julia Schulda, Zacharias Orfanosa, Rudolf A. Kleyd, Rudolf Volkmerc, Matthias Wilmannsb, Gregor Kirfela, Peter F. M. van der Vena, and Dieter O. Fürsta aInstitute for Cell Biology, University of Bonn, D-53121 Bonn, Germany; bEuropean Molecular Biology Laboratory- Hamburg/Deutsches Elektronen-Synchrotron, D-22603 Hamburg, Germany; cDepartment of Medicinal Immunology, Charité-University Medicine Berlin, D-13353 Berlin, Germany; dDepartment of Neurology, Neuromuscular Center Ruhrgebiet, University Hospital Bergmannsheil, Ruhr-University Bochum, D-44789 Bochum, Germany ABSTRACT The Xin actin-binding repeat–containing proteins Xin and XIRP2 are exclusively Monitoring Editor expressed in striated muscle cells, where they are believed to play an important role in devel- Laurent Blanchoin opment. In adult muscle, both proteins are concentrated at attachment sites of myofibrils to CEA Grenoble the membrane. In contrast, during development they are localized to immature myofibrils Received: Apr 22, 2013 together with their binding partner, filamin C, indicating an involvement of both proteins in Revised: Jul 26, 2013 myofibril assembly. We identify the SH3 domains of nebulin and nebulette as novel ligands of Accepted: Aug 19, 2013 proline-rich regions of Xin and XIRP2. Precise binding motifs are mapped and shown to bind both SH3 domains with micromolar affinity. Cocrystallization of the nebulette SH3 domain with the interacting XIRP2 peptide PPPTLPKPKLPKH reveals selective interactions that con- form to class II SH3 domain–binding peptides. -
Comparative Gene Expression Profiling Between Human Cultured
Raymond et al. BMC Genomics 2010, 11:125 http://www.biomedcentral.com/1471-2164/11/125 RESEARCH ARTICLE Open Access Comparative gene expression profiling between human cultured myotubes and skeletal muscle tissue Frederic Raymond1, Sylviane Métairon1, Martin Kussmann1, Jaume Colomer2, Andres Nascimento2, Emma Mormeneo3, Cèlia García-Martínez3, Anna M Gómez-Foix3* Abstract Background: A high-sensitivity DNA microarray platform requiring nanograms of RNA input facilitates the application of transcriptome analysis to individual skeletal muscle (SM) tissue samples. Culturing myotubes from SM-biopsies enables investigating transcriptional defects and assaying therapeutic strategies. This study compares the transcriptome of aneurally cultured human SM cells versus that of tissue biopsies. Results: We used the Illumina expression BeadChips to determine the transcriptomic differences between tissue and cultured SM samples from five individuals. Changes in the expression of several genes were confirmed by QuantiGene Plex assay or reverse transcription real-time PCR. In cultured myotubes compared to the tissue, 1216 genes were regulated: 583 down and 633 up. Gene ontology analysis showed that downregulated genes were mainly associated with cytoplasm, particularly mitochondria, and involved in metabolism and the muscle-system/ contraction process. Upregulated genes were predominantly related to cytoplasm, endoplasmic reticulum, and extracellular matrix. The most significantly regulated pathway was mitochondrial dysfunction. Apoptosis genes were also modulated. Among the most downregulated genes detected in this study were genes encoding metabolic proteins AMPD1, PYGM, CPT1B and UCP3, muscle-system proteins TMOD4, MYBPC1, MYOZ1 and XIRP2, the proteolytic CAPN3 and the myogenic regulator MYF6. Coordinated reduced expression of five members of the GIMAP gene family, which form a cluster on chromosome 7, was shown, and the GIMAP4-reduction was validated. -
Roles of Nebulin Family Members in the Heart Marie-Louise Bang, Phd; Ju Chen, Phd
Advance Publication by-J-STAGE Circulation Journal REVIEW Official Journal of the Japanese Circulation Society http://www.j-circ.or.jp Roles of Nebulin Family Members in the Heart Marie-Louise Bang, PhD; Ju Chen, PhD The members of the nebulin protein family, including nebulin, nebulette, LASP-1, LASP-2, and N-RAP, contain various numbers of nebulin repeats and bind to actin, but are otherwise heterogeneous with regard to size, expres- sion pattern, and function. This review focuses on the roles of nebulin family members in the heart. Nebulin is the largest member predominantly expressed in skeletal muscle, where it stretches along the thin filament. In heart, nebulin is detectable only at low levels and its absence has no apparent effects. Nebulette is similar in structure to the nebulin C-terminal Z-line region and specifically expressed in heart. Nebulette gene mutations have been iden- tified in dilated cardiomyopathy patients and transgenic mice overexpressing nebulette mutants partially recapitulate the human pathology. In contrast, nebulette knockout mice show no functional phenotype, but exhibit Z-line widen- ing. LASP-2 is an isoform of nebulette expressed in multiple tissues, including the heart. It is present in the Z-line and intercalated disc and able to bind and cross-link filamentous actin. LASP-1 is similar in structure to LASP-2, but expressed only in non-muscle tissue. N-RAP is present in myofibril precursors during myofibrillogenesis and thought to be involved in myofibril assembly, while it is localized at the intercalated disc in adult heart. Additional in vivo models are required to provide further insights into the functions of nebulin family members in the heart. -
Transposon Mutagenesis Identifies Genetic Drivers of Brafv600e Melanoma
ARTICLES Transposon mutagenesis identifies genetic drivers of BrafV600E melanoma Michael B Mann1,2, Michael A Black3, Devin J Jones1, Jerrold M Ward2,12, Christopher Chin Kuan Yew2,12, Justin Y Newberg1, Adam J Dupuy4, Alistair G Rust5,12, Marcus W Bosenberg6,7, Martin McMahon8,9, Cristin G Print10,11, Neal G Copeland1,2,13 & Nancy A Jenkins1,2,13 Although nearly half of human melanomas harbor oncogenic BRAFV600E mutations, the genetic events that cooperate with these mutations to drive melanogenesis are still largely unknown. Here we show that Sleeping Beauty (SB) transposon-mediated mutagenesis drives melanoma progression in BrafV600E mutant mice and identify 1,232 recurrently mutated candidate cancer genes (CCGs) from 70 SB-driven melanomas. CCGs are enriched in Wnt, PI3K, MAPK and netrin signaling pathway components and are more highly connected to one another than predicted by chance, indicating that SB targets cooperative genetic networks in melanoma. Human orthologs of >500 CCGs are enriched for mutations in human melanoma or showed statistically significant clinical associations between RNA abundance and survival of patients with metastatic melanoma. We also functionally validate CEP350 as a new tumor-suppressor gene in human melanoma. SB mutagenesis has thus helped to catalog the cooperative molecular mechanisms driving BRAFV600E melanoma and discover new genes with potential clinical importance in human melanoma. Substantial sun exposure and numerous genetic factors, including including BrafV600E, recapitulate the genetic and histological hallmarks skin type and family history, are the most important melanoma risk of human melanoma. In these models, increased MEK-ERK signaling factors. Familial melanoma, which accounts for <10% of cases, is asso- initiates clonal expansion of melanocytes, which is limited by oncogene- ciated with mutations in CDKN2A1, MITF2 and POT1 (refs.