A Single-Cell Transcriptomic Landscape of Primate Arterial Aging
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Versican V2 Assembles the Extracellular Matrix Surrounding the Nodes of Ranvier in the CNS
The Journal of Neuroscience, June 17, 2009 • 29(24):7731–7742 • 7731 Cellular/Molecular Versican V2 Assembles the Extracellular Matrix Surrounding the Nodes of Ranvier in the CNS María T. Dours-Zimmermann,1 Konrad Maurer,2 Uwe Rauch,3 Wilhelm Stoffel,4 Reinhard Fa¨ssler,5 and Dieter R. Zimmermann1 Institutes of 1Surgical Pathology and 2Anesthesiology, University Hospital Zurich, CH-8091 Zurich, Switzerland, 3Vascular Wall Biology, Department of Experimental Medical Science, University of Lund, S-221 00 Lund, Sweden, 4Center for Biochemistry, Medical Faculty, University of Cologne, D-50931 Cologne, Germany, and 5Department of Molecular Medicine, Max Planck Institute of Biochemistry, D-82152 Martinsried, Germany The CNS-restricted versican splice-variant V2 is a large chondroitin sulfate proteoglycan incorporated in the extracellular matrix sur- rounding myelinated fibers and particularly accumulating at nodes of Ranvier. In vitro, it is a potent inhibitor of axonal growth and therefore considered to participate in the reduction of structural plasticity connected to myelination. To study the role of versican V2 during postnatal development, we designed a novel isoform-specific gene inactivation approach circumventing early embryonic lethality of the complete knock-out and preventing compensation by the remaining versican splice variants. These mice are viable and fertile; however, they display major molecular alterations at the nodes of Ranvier. While the clustering of nodal sodium channels and paranodal structures appear in versican V2-deficient mice unaffected, the formation of the extracellular matrix surrounding the nodes is largely impaired. The conjoint loss of tenascin-R and phosphacan from the perinodal matrix provide strong evidence that versican V2, possibly controlled by a nodal receptor, organizes the extracellular matrix assembly in vivo. -
The Role of Glypicans in Wnt Inhibitory Factor-1 Activity and the Structural Basis of Wif1’S Effects on Wnt and Hedgehog Signaling
The Role of Glypicans in Wnt Inhibitory Factor-1 Activity and the Structural Basis of Wif1’s Effects on Wnt and Hedgehog Signaling Andrei Avanesov1,2, Shawn M. Honeyager1, Jarema Malicki3, Seth S. Blair1* 1 Department of Zoology, University of Wisconsin, Madison, Wisconsin, United States of America, 2 Genetics Training Program, University of Wisconsin, Madison, Wisconsin, United States of America, 3 Division of Craniofacial and Molecular Genetics, Tufts University, Boston, Massachusetts, United States of America Abstract Proper assignment of cellular fates relies on correct interpretation of Wnt and Hedgehog (Hh) signals. Members of the Wnt Inhibitory Factor-1 (WIF1) family are secreted modulators of these extracellular signaling pathways. Vertebrate WIF1 binds Wnts and inhibits their signaling, but its Drosophila melanogaster ortholog Shifted (Shf) binds Hh and extends the range of Hh activity in the developing D. melanogaster wing. Shf activity is thought to depend on reinforcing interactions between Hh and glypican HSPGs. Using zebrafish embryos and the heterologous system provided by D. melanogaster wing, we report on the contribution of glypican HSPGs to the Wnt-inhibiting activity of zebrafish Wif1 and on the protein domains responsible for the differences in Wif1 and Shf specificity. We show that Wif1 strengthens interactions between Wnt and glypicans, modulating the biphasic action of glypicans towards Wnt inhibition; conversely, glypicans and the glypican- binding ‘‘EGF-like’’ domains of Wif1 are required for Wif1’s full Wnt-inhibiting activity. Chimeric constructs between Wif1 and Shf were used to investigate their specificities for Wnt and Hh signaling. Full Wnt inhibition required the ‘‘WIF’’ domain of Wif1, and the HSPG-binding EGF-like domains of either Wif1 or Shf. -
Ccdc80 and Ccdc80-L1: Identification and Functional Analysis of Two Novel Genes Involved in Zebrafish (Danio Rerio) Development
UNIVERSITÀ DEGLI STUDI DI MILANO SCUOLA DI DOTTORATO IN SCIENZE BIOLOGICHE E MOLECOLARI DIPARTIMENTO DI BIOLOGIA DOTTORATO DI RICERCA IN BIOLOGIA CELLULARE E MOLECOLARE XXIV CICLO ccdc80 and ccdc80-l1: Identification and Functional Analysis of Two Novel Genes Involved in Zebrafish (Danio rerio) Development settori scientifico/disciplinari: BIO/06; BIO/11 Tesi di dottorato di Chiara Brusegan R08215 TUTOR: prof. Franco Cotelli COORDINATORE DEL DOTTORATO: prof. Martino Bolognesi A.A. 2010/2011 Index Part I 1. Abstract 1 2. State of the art 2 2.1 Motility of the zebrafish embryo 2 2.2 Muscle formation 3 2.3 Neural differentiation 6 2.4 Identification of zebrafish ccdc80 genes 9 3. Aim of the project 13 4. Materials and Methods 14 4.1 Zebrafish lines and maintenance 14 4.2 Sequence analysis 14 4.3 RT-PCR 15 4.4 Synthesis of probes for whole mount in situ hybridization (WISH) 16 4.5 Whole-mount in situ hybridization 17 4.6 Immunohistochemistry 17 4.7 Histological sections 18 4.8 Injections 18 4.9 Cyclopamine treatment 19 4.10 Statistical analysis 19 5. Results 20 5.1 Identification of ccdc80 homologs in the genome of zebrafish 20 5.2.1 ccdc80 expression profiling 22 5.2.2 ccdc80-loss- and gain-of-function affects somitogenesis in vivo 23 5.2.3 ccdc80 is involved in somitogenesis, but not in the development of the notochord 25 5.2.4 ccdc80 is positively regulated by the Hedgehog pathway 26 5.3.1 ccdc80-l1 expression profiling 27 5.3.2 ccdc80-l1 knocked-down embryos displayed impaired motility 29 5.3.3 ccdc80-l1 loss of function does not affect somitogenesis nor muscle pioneers and adaxial cells formation 30 5.3.4 analysis of neurogenesis of primary motoneurons in ccdc80-l1 morphants 32 5.3.5 Also ccdc80-l1 expression is positively regulated by the Hedgehog pathway 35 5.4.1 ccdc80 expression is not regulated by ccdc80-l1, nor vice versa 37 6. -
PLZF Targets Developmental Enhancers for Activation During Osteogenic Differentiation of Human Mesenchymal Stem Cells
RESEARCH ARTICLE PLZF targets developmental enhancers for activation during osteogenic differentiation of human mesenchymal stem cells Shuchi Agrawal Singh1,2,3*, Mads Lerdrup1,3, Ana-Luisa R Gomes1,3, Harmen JG van de Werken4,5,6, Jens Vilstrup Johansen1,3,7, Robin Andersson1,3,7, Albin Sandelin1,3,7, Kristian Helin8,9,10, Klaus Hansen1,3* 1Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 2Department of Hematology, Cambridge Institute for Medical Research and Welcome Trust/MRC Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom; 3Centre for Epigenetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 4Department of Cell Biology, University Medical Center, Rotterdam, Netherlands; 5Cancer Computational Biology Center, University Medical Center, Rotterdam, Netherlands; 6Department of Urology, University Medical Center, Rotterdam, Netherlands; 7Department of Biology, The Bioinformatics Centre, University of Copenhagen, Copenhagen, Denmark; 8The Novo Nordisk Center for Stem Cell Biology, Faculty of Health and Medical Sciences University of Copenhagen, Copenhagen, Denmark; 9Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States; 10Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, United States *For correspondence: [email protected]; Abstract The PLZF transcription factor is essential for osteogenic differentiation of hMSCs; [email protected] (SAS); however, its regulation and molecular function during this process is not fully understood. Here, we [email protected] (KHA) revealed that the ZBTB16 locus encoding PLZF, is repressed by Polycomb (PcG) and H3K27me3 in Competing interests: The naive hMSCs. At the pre-osteoblast stage of differentiation, the locus lost PcG binding and authors declare that no H3K27me3, gained JMJD3 recruitment, and H3K27ac resulting in high expression of PLZF. -
V10a91-Tasheva Pgmkr
Molecular Vision 2004; 10:758-772 <http://www.molvis.org/molvis/v10/a91> ©2004 Molecular Vision Received 12 August 2004 | Accepted 7 October 2004 | Published 7 October 2004 Analysis of transcriptional regulation of the small leucine rich proteoglycans Elena S. Tasheva,1 Bernward Klocke,2 Gary W. Conrad1 1Kansas State University, Division of Biology, Manhattan, KS; 2Genomatix Software GmbH, München, Germany Purpose: Small leucine rich proteoglycans (SLRPs) constitute a family of secreted proteoglycans that are important for collagen fibrillogenesis, cellular growth, differentiation, and migration. Ten of the 13 known members of the SLRP gene family are arranged in tandem clusters on human chromosomes 1, 9, and 12. Their syntenic equivalents are on mouse chromosomes 1, 13, and 10, and rat chromosomes 13, 17, and 7. The purpose of this study was to determine whether there is evidence for control elements, which could regulate the expression of these clusters coordinately. Methods: Promoters were identified using a comparative genomics approach and Genomatix software tools. For each gene a set of human, mouse, and rat orthologous promoters was extracted from genomic sequences. Transcription factor (TF) binding site analysis combined with a literature search was performed using MatInspector and Genomatix’ BiblioSphere. Inspection for the presence of interspecies conserved scaffold/matrix attachment regions (S/MARs) was performed using ElDorado annotation lists. DNAseI hypersensitivity assay, chromatin immunoprecipitation (ChIP), and transient transfection experiments were used to validate the results from bioinformatics analysis. Results: Transcription factor binding site analysis combined with a literature search revealed co-citations between several SLRPs and TFs Runx2 and IRF1, indicating that these TFs have potential roles in transcriptional regulation of the SLRP family members. -
Kids First Pediatric Research Program (Kids First) Poster Session at ASHG Accelerating Pediatric Genomics Research Through Collaboration October 15Th, 2019
The Gabriella Miller Kids First Pediatric Research Program (Kids First) Poster Session at ASHG Accelerating Pediatric Genomics Research through Collaboration October 15th, 2019 Background The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans- NIH Common Fund program initiated in response to the 2014 Gabriella Miller Kids First Research Act. The program’s vision is to alleviate suffering from childhood cancer and structural birth defects by fostering collaborative research to uncover the etiology of these diseases and support data sharing within the pediatric research community. This is implemented through developing the Gabriella Miller Kids First Data Resource (Kids First Data Resource) and populating this resource with whole genome sequence datasets and associated clinical and phenotypic information. Both childhood cancers and structural birth defects are critical and costly conditions associated with substantial morbidity and mortality. Elucidating the underlying genetic etiology of these diseases has the potential to profoundly improve preventative measures, diagnostics, and therapeutic interventions. Purpose During this evening poster session, attendees will gain a broad understanding of the utility of the genomic data generated by Kids First, learn about the progress of Kids First X01 cohort projects, and observe demonstrations of the tools and functionalities of the recently launched Kids First Data Resource Portal. The session is an opportunity for the scientific community and public to engage with Kids First investigators, collaborators, and a growing community of researchers, patient foundations, and families. Several other NIH and external data efforts will present posters and be available to discuss collaboration opportunities as we work together to accelerate pediatric research. -
A Molecular and Genetic Analysis of Otosclerosis
A molecular and genetic analysis of otosclerosis Joanna Lauren Ziff Submitted for the degree of PhD University College London January 2014 1 Declaration I, Joanna Ziff, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. Where work has been conducted by other members of our laboratory, this has been indicated by an appropriate reference. 2 Abstract Otosclerosis is a common form of conductive hearing loss. It is characterised by abnormal bone remodelling within the otic capsule, leading to formation of sclerotic lesions of the temporal bone. Encroachment of these lesions on to the footplate of the stapes in the middle ear leads to stapes fixation and subsequent conductive hearing loss. The hereditary nature of otosclerosis has long been recognised due to its recurrence within families, but its genetic aetiology is yet to be characterised. Although many familial linkage studies and candidate gene association studies to investigate the genetic nature of otosclerosis have been performed in recent years, progress in identifying disease causing genes has been slow. This is largely due to the highly heterogeneous nature of this condition. The research presented in this thesis examines the molecular and genetic basis of otosclerosis using two next generation sequencing technologies; RNA-sequencing and Whole Exome Sequencing. RNA–sequencing has provided human stapes transcriptomes for healthy and diseased stapes, and in combination with pathway analysis has helped identify genes and molecular processes dysregulated in otosclerotic tissue. Whole Exome Sequencing has been employed to investigate rare variants that segregate with otosclerosis in affected families, and has been followed by a variant filtering strategy, which has prioritised genes found to be dysregulated during RNA-sequencing. -
Sequence Analysis of Familial Neurodevelopmental Disorders
SEQUENCE ANALYSIS OF FAMILIAL NEURODEVELOPMENTAL DISORDERS by Joseph Mark Tilghman A dissertation submitted to Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland December 2020 © 2020 Joseph Tilghman All Rights Reserved Abstract: In the practice of human genetics, there is a gulf between the study of Mendelian and complex inheritance. When diagnosis of families affected by presumed monogenic syndromes is undertaken by genomic sequencing, these families are typically considered to have been solved only when a single gene or variant showing apparently Mendelian inheritance is discovered. However, about half of such families remain unexplained through this approach. On the other hand, common regulatory variants conferring low risk of disease still predominate our understanding of individual disease risk in complex disorders, despite rapidly increasing access to rare variant genotypes through sequencing. This dissertation utilizes primarily exome sequencing across several developmental disorders (having different levels of genetic complexity) to investigate how to best use an individual’s combination of rare and common variants to explain genetic risk, phenotypic heterogeneity, and the molecular bases of disorders ranging from those presumed to be monogenic to those known to be highly complex. The study described in Chapter 2 addresses putatively monogenic syndromes, where we used exome sequencing of four probands having syndromic neurodevelopmental disorders from an Israeli-Arab founder population to diagnose recessive and dominant disorders, highlighting the need to consider diverse modes of inheritance and phenotypic heterogeneity. In the study described in Chapter 3, we address the case of a relatively tractable multifactorial disorder, Hirschsprung disease. -
Mir-552: an Important Post-Transcriptional Regulator That Affects Human Cancer Yuhao Zou, Xin Zhao, Yin Li, Shiwei Duan
Journal of Cancer 2020, Vol. 11 6226 Ivyspring International Publisher Journal of Cancer 2020; 11(21): 6226-6233. doi: 10.7150/jca.46613 Review miR-552: an important post-transcriptional regulator that affects human cancer Yuhao Zou, Xin Zhao, Yin Li, Shiwei Duan Medical Genetics Center, Ningbo University School of Medicine, Ningbo, Zhejiang, China. Corresponding authors: Shiwei Duan (E-mail: [email protected]) and Dr. Xin Zhao (E-mail: [email protected]). © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. Received: 2020.04.02; Accepted: 2020.08.14; Published: 2020.08.27 Abstract MiR-552 is a small non-coding RNA located on chromosome 1p34.3, and its expression level is significantly up-regulated in tissues or cells of various tumors. miR-552 can target multiple genes. These targeted genes play important regulatory roles in biological processes such as gene transcription and translation, cell cycle progression, cell proliferation, apoptosis, cell migration, and invasion. Besides, miR-552 may affect the efficacy of various anticancer drugs by targeting genes such as TP53 and RUNX3. This review summarizes the biological functions and clinical expressions of miR-552 in human cancer. Our goal is to explore the potential value of miR-552 in the diagnosis, prognosis, and treatment of human cancer. Key words: miR-552; cancer; diagnosis; prognosis; drug resistance Introduction MicroRNAs (miRNAs) are a class of non-coding small RNAs with a length of about 22 bp. -
Systematic Detection of Divergent Brain Proteins in Human Evolution and Their Roles in Cognition
bioRxiv preprint doi: https://doi.org/10.1101/658658; this version posted June 3, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Systematic detection of divergent brain proteins in human evolution and their roles in cognition Guillaume Dumas1,*, Simon Malesys1 and Thomas Bourgeron1 Affiliations: 1 Human Genetics and Cognitive Functions, Institut Pasteur, UMR3571 CNRS, Université de Paris, Paris, (75015) France * Corresponding author: [email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/658658; this version posted June 3, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Abstract The human brain differs from that of other primates, but the underlying genetic mechanisms remain unclear. Here we measured the evolutionary pressures acting on all human protein- coding genes (N=17,808) based on their divergence from early hominins such as Neanderthal, and non-human primates. We confirm that genes encoding brain-related proteins are among the most conserved of the human proteome. Conversely, several of the most divergent proteins in humans compared to other primates are associated with brain-associated diseases such as micro/macrocephaly, dyslexia, and autism. We identified specific eXpression profiles of a set of divergent genes in ciliated cells of the cerebellum, that might have contributed to the emergence of fine motor skills and social cognition in humans. -
5' Untranslated Region Elements Show High Abundance and Great
International Journal of Molecular Sciences Article 0 5 Untranslated Region Elements Show High Abundance and Great Variability in Homologous ABCA Subfamily Genes Pavel Dvorak 1,2,* , Viktor Hlavac 2,3 and Pavel Soucek 2,3 1 Department of Biology, Faculty of Medicine in Pilsen, Charles University, 32300 Pilsen, Czech Republic 2 Biomedical Center, Faculty of Medicine in Pilsen, Charles University, 32300 Pilsen, Czech Republic; [email protected] (V.H.); [email protected] (P.S.) 3 Toxicogenomics Unit, National Institute of Public Health, 100 42 Prague, Czech Republic * Correspondence: [email protected]; Tel.: +420-377593263 Received: 7 October 2020; Accepted: 20 November 2020; Published: 23 November 2020 Abstract: The 12 members of the ABCA subfamily in humans are known for their ability to transport cholesterol and its derivatives, vitamins, and xenobiotics across biomembranes. Several ABCA genes are causatively linked to inborn diseases, and the role in cancer progression and metastasis is studied intensively. The regulation of translation initiation is implicated as the major mechanism in the processes of post-transcriptional modifications determining final protein levels. In the current bioinformatics study, we mapped the features of the 50 untranslated regions (50UTR) known to have the potential to regulate translation, such as the length of 50UTRs, upstream ATG codons, upstream open-reading frames, introns, RNA G-quadruplex-forming sequences, stem loops, and Kozak consensus motifs, in the DNA sequences of all members of the subfamily. Subsequently, the conservation of the features, correlations among them, ribosome profiling data as well as protein levels in normal human tissues were examined. The 50UTRs of ABCA genes contain above-average numbers of upstream ATGs, open-reading frames and introns, as well as conserved ones, and these elements probably play important biological roles in this subfamily, unlike RG4s. -
S41467-020-18249-3.Pdf
ARTICLE https://doi.org/10.1038/s41467-020-18249-3 OPEN Pharmacologically reversible zonation-dependent endothelial cell transcriptomic changes with neurodegenerative disease associations in the aged brain Lei Zhao1,2,17, Zhongqi Li 1,2,17, Joaquim S. L. Vong2,3,17, Xinyi Chen1,2, Hei-Ming Lai1,2,4,5,6, Leo Y. C. Yan1,2, Junzhe Huang1,2, Samuel K. H. Sy1,2,7, Xiaoyu Tian 8, Yu Huang 8, Ho Yin Edwin Chan5,9, Hon-Cheong So6,8, ✉ ✉ Wai-Lung Ng 10, Yamei Tang11, Wei-Jye Lin12,13, Vincent C. T. Mok1,5,6,14,15 &HoKo 1,2,4,5,6,8,14,16 1234567890():,; The molecular signatures of cells in the brain have been revealed in unprecedented detail, yet the ageing-associated genome-wide expression changes that may contribute to neurovas- cular dysfunction in neurodegenerative diseases remain elusive. Here, we report zonation- dependent transcriptomic changes in aged mouse brain endothelial cells (ECs), which pro- minently implicate altered immune/cytokine signaling in ECs of all vascular segments, and functional changes impacting the blood–brain barrier (BBB) and glucose/energy metabolism especially in capillary ECs (capECs). An overrepresentation of Alzheimer disease (AD) GWAS genes is evident among the human orthologs of the differentially expressed genes of aged capECs, while comparative analysis revealed a subset of concordantly downregulated, functionally important genes in human AD brains. Treatment with exenatide, a glucagon-like peptide-1 receptor agonist, strongly reverses aged mouse brain EC transcriptomic changes and BBB leakage, with associated attenuation of microglial priming. We thus revealed tran- scriptomic alterations underlying brain EC ageing that are complex yet pharmacologically reversible.