DOCSLIB.ORG

Common and Distinct DNA-Binding and Regulatory Activities of the BEN-Solo Transcription Factor Family

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Common and Distinct DNA-Binding and Regulatory Activities of the BEN-Solo Transcription Factor Family Downloaded from genesdev.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press Common and distinct DNA-binding and regulatory activities of the BEN-solo transcription factor family Qi Dai,1 Aiming Ren,2 Jakub O. Westholm,1,3 Hong Duan,1 Dinshaw J. Patel,2 and Eric C. Lai1 1Department of Developmental Biology, 2Department of Structural Biology, Sloan-Kettering Institute New York, New York 10065, USA Recently, the BEN (BANP, E5R, and NAC1) domain was recognized as a new class of conserved DNA-binding domain. The fly genome encodes three proteins that bear only a single BEN domain (‘‘BEN-solo’’ factors); namely, Insensitive (Insv), Bsg25A (Elba1), and CG9883 (Elba2). Insv homodimers preferentially bind CCAATTGG palindromes throughout the genome to mediate transcriptional repression, whereas Bsg25A and Elba2 hetero- trimerize with their obligate adaptor, Elba3 (i.e., the ELBA complex), to recognize a CCAATAAG motif in the Fab-7 insulator. While these data suggest distinct DNA-binding properties of BEN-solo proteins, we performed reporter assays that indicate that both Bsg25A and Elba2 can individually recognize Insv consensus sites efficiently. We confirmed this by solving the structure of Bsg25A complexed to the Insv site, which showed that key aspects of the BEN:DNA recognition strategy are similar between these proteins. We next show that both Insv and ELBA proteins are competent to mediate transcriptional repression via Insv consensus sequences but that the ELBA complex appears to be selective for the ELBA site. Reciprocally, genome-wide analysis reveals that Insv exhibits significant cobinding to class I insulator elements, indicating that it may also contribute to insulator function. Indeed, we observed abundant Insv binding within the Hox complexes with substantial overlaps with class I insulators, many of which bear Insv consensus sites. Moreover, Insv coimmunoprecipitates with the class I insulator factor CP190. Finally, we observed that Insv harbors exclusive activity among fly BEN-solo factors with respect to regulation of Notch-mediated cell fate choices in the peripheral nervous system. This in vivo activity is recapitulated by BEND6, a mammalian BEN-solo factor that conserves the Notch corepressor function of Insv but not its capacity to bind Insv consensus sites. Altogether, our data define an array of common and distinct biochemical and functional properties of this new family of transcription factors. [Keywords: BEN-solo; insulator; repressor; transcription factor] Supplemental material is available for this article. Received September 2, 2014; revised version accepted November 20, 2014. The BEN (BANP, E5R, and NAC1) domain was originally (NAC1), or interacting with insulator sites [mod(mdg4)] or identified bioinformatically as a domain with a-helical heterochromatin (BEND3). Altogether, these collected character that is present in a variety of metazoan and viral findings indicate an intimate connection between diverse proteins (Abhiman et al. 2008). Several BEN-containing BEN proteins and gene repression. proteins were characterized to have chromatin-related Previous studies of BEN proteins mostly concern functions, including mammalian BANP/SMAR1 (Kaul- factors that contain other characterized domains, and, Ghanekar et al. 2004; Rampalli et al. 2005), NAC1 (Korutla in these cases, the function of the BEN domain has not et al. 2005, 2007), BEND3 (Sathyan et al. 2011), and the C received much attention (Abhiman et al. 2008). Recently, isoform of Drosophila mod(mdg4) (Gerasimova et al. 1995; several studies indicate a new functionality for the BEN Negre et al. 2010). Moreover, all of these proteins were domain as an intrinsic sequence-specific DNA-binding linked to transcriptional silencing, albeit via different domain. Mammalian RBB, a BEN and BTB domain strategies such as interacting with matrix attachment protein, was found as a direct transcriptional repressor of sites (SMAR1), recruiting histone deacetylases or CoREST Ó 2015 Dai et al. This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue 3Present address: Science for Life Laboratory, Department of Biochem- publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). istry and Biophysics, Stockholm University, SE-17121 Solna, Sweden. After six months, it is available under a Creative Commons License Corresponding author: [email protected] (Attribution-NonCommercial 4.0 International), as described at http:// Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.252122.114. creativecommons.org/licenses/by-nc/4.0/. 48 GENES & DEVELOPMENT 29:48–62 Published by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/15; www.genesdev.org Downloaded from genesdev.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press Drosophila BEN-solo proteins the HDM2 oncogene and an interactor of the nucleosome with the capacity to regulate Notch signaling during periph- remodeling and deacetylase (NuRD) complex (Xuan et al. eral neurogenesis. Indeed, mammalian BEND6 is better 2013). In vitro selection tests showed that RBB bound able to rescue neural phenotypes of flies compromised for DNA as a homodimer to TGTCRSWWYYGWC-type sites. CSL corepressor function than ELBA factors are. Alto- Two other studies in Drosophila provided the first func- gether, we identified both distinct and overlapping functional tional analyses of the subclass of BEN proteins that properties of the three Drosophila BEN-solo proteins, contain only a single BEN domain and no other recogniz- introducing unexpected complexity in their contribu- able domains (i.e., ‘‘BEN-solo’’ proteins). Two of these tions to gene regulation and development. proteins, Bsg25A (Elba1) and CG9883 (Elba2), along with the adaptor protein CG15634 (Elba3) associate with the Results asymmetric site ‘‘CCAATAAG’’ in the Fab-7 insulator element and are involved in insulator function (Aoki et al. The neural BEN-solo factor Insv is deployed 2012). In vitro gel shift assays demonstrated that DNA- throughout the blastoderm with ELBA factors binding activity on this site is a specific attribute of the Of the three Drosophila BEN-solo factors, Elba1 (Bsg25A) heterotrimeric complex, with no binding being observed and Elba2 (CG9883) reside in the ELBA heterotrimeric by any pairwise or single proteins tested. Genome-wide complex (Aoki et al. 2012). In this study, we chose to studies of the third Drosophila BEN-solo factor, Insensi- retain the Bsg25A nomenclature due to historical pre- tive (Insv), showed its broad genomic association with cedent (Singer and Lengyel 1997) and refer to the other TCYAATHRGAA sites, and in vitro studies demonstrated Elba BEN-solo component as Elba2. As noted, Bsg25A and high-affinity binding of Insv homodimers to palindromic Elba3 reside in neighboring transcription units (with TCCAATTGGA sequences (Dai et al. 2013b). Reporter Bsg25A nested within CG11929), while the BEN-solo studies in culture cells and expression profiling of insv loci Insv and Elba2 are also arranged as adjacent genomic mutants indicate that Insv binding to its cognate site loci (Aoki et al. 2012). mediates transcriptional repression. Our previous Insv immunostaining studies during Curiously, Insv exhibits dual modes of transcriptional larval and pupal stages highlighted its restricted spatial regulation. In addition to functioning as a direct repressor, accumulation in the developing peripheral nervous sys- it is also recruited to chromatin via a CSL-type transcrip- tem (PNS) for adult mechanosensory organs (Duan et al. tion factor, which serves as the primary nuclear effector of 2011), consistent with studies of insv mRNA accumulation the Notch signaling pathway (Lai 2004). In this context, (Reeves and Posakony 2005). These patterns are seemingly Insv associates directly with CSL via its BEN domain, distinct from the documented ubiquitous blastoderm ex- represses Notch pathway target genes, and is required pression of various ELBA factors. However, inspection of phenotypically to oppose Notch signaling during neural modENCODE developmental time-course RNA sequenc- cell fate specification and promote neurogenesis (Duan ing (RNA-seq) data (Graveley et al. 2011) indicated that et al. 2011). Although a definitive mammalian ortholog of insv mRNA levels are by far highest in 2- to 4-h embryos Insv is not apparent from the primary sequence, mamma- (Fig. 1A). Indeed, we confirmed strong ubiquitous accu- lian BEND6 has all of the key functional attributes of mulation of Insv protein in blastoderm stages (Fig. 1B). a CSL corepressor. In particular, BEND6 binds CSL di- Thus, Insv exhibits two phases of expression: early/ubiqui- rectly via its BEN domain, associates with and represses tous and later/neural-restricted (Fig. 1B–G). Notably, peak Notch target genes, and restricts Notch signaling in neural levels of Bsg25A, Elba2, and Elba3 are also found specif- stem cells, thereby opposing their self-renewal and pro- ically in 2- to 4-h embryos (Fig 1A). We confirmed the strong moting neurogenesis (Dai et al. 2013a). and specific blastoderm expression of Bsg25A and Elba3 These collected studies suggest that Insv and Elba proteins (Supplemental Fig. 1) and note that the presence exhibit distinct sequence preferences and strategies of of Elba2 in later embryonic stages corresponds mostly to DNA binding (homodimer vs. heterotrimer) and that this its expression in the procephalic ectoderm primordium may be further associated
Load more

Recommended publications
  • Location Analysis of Estrogen Receptor Target Promoters Reveals That
    Location analysis of estrogen receptor ␣ target promoters reveals that FOXA1 defines a domain of the estrogen response Jose´ e Laganie` re*†, Genevie` ve Deblois*, Ce´ line Lefebvre*, Alain R. Bataille‡, Franc¸ois Robert‡, and Vincent Gigue` re*†§ *Molecular Oncology Group, Departments of Medicine and Oncology, McGill University Health Centre, Montreal, QC, Canada H3A 1A1; †Department of Biochemistry, McGill University, Montreal, QC, Canada H3G 1Y6; and ‡Laboratory of Chromatin and Genomic Expression, Institut de Recherches Cliniques de Montre´al, Montreal, QC, Canada H2W 1R7 Communicated by Ronald M. Evans, The Salk Institute for Biological Studies, La Jolla, CA, July 1, 2005 (received for review June 3, 2005) Nuclear receptors can activate diverse biological pathways within general absence of large scale functional data linking these putative a target cell in response to their cognate ligands, but how this binding sites with gene expression in specific cell types. compartmentalization is achieved at the level of gene regulation is Recently, chromatin immunoprecipitation (ChIP) has been used poorly understood. We used a genome-wide analysis of promoter in combination with promoter or genomic DNA microarrays to occupancy by the estrogen receptor ␣ (ER␣) in MCF-7 cells to identify loci recognized by transcription factors in a genome-wide investigate the molecular mechanisms underlying the action of manner in mammalian cells (20–24). This technology, termed 17␤-estradiol (E2) in controlling the growth of breast cancer cells. ChIP-on-chip or location analysis, can therefore be used to deter- We identified 153 promoters bound by ER␣ in the presence of E2. mine the global gene expression program that characterize the Motif-finding algorithms demonstrated that the estrogen re- action of a nuclear receptor in response to its natural ligand.
    [Show full text]
  • A Private 16Q24.2Q24.3 Microduplication in a Boy with Intellectual Disability, Speech Delay and Mild Dysmorphic Features
    G C A T T A C G G C A T genes Article A Private 16q24.2q24.3 Microduplication in a Boy with Intellectual Disability, Speech Delay and Mild Dysmorphic Features Orazio Palumbo * , Pietro Palumbo , Ester Di Muro, Luigia Cinque, Antonio Petracca, Massimo Carella and Marco Castori Division of Medical Genetics, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, 71013 Foggia, Italy; [email protected] (P.P.); [email protected] (E.D.M.); [email protected] (L.C.); [email protected] (A.P.); [email protected] (M.C.); [email protected] (M.C.) * Correspondence: [email protected]; Tel.: +39-088-241-6350 Received: 5 June 2020; Accepted: 24 June 2020; Published: 26 June 2020 Abstract: No data on interstitial microduplications of the 16q24.2q24.3 chromosome region are available in the medical literature and remain extraordinarily rare in public databases. Here, we describe a boy with a de novo 16q24.2q24.3 microduplication at the Single Nucleotide Polymorphism (SNP)-array analysis spanning ~2.2 Mb and encompassing 38 genes. The patient showed mild-to-moderate intellectual disability, speech delay and mild dysmorphic features. In DECIPHER, we found six individuals carrying a “pure” overlapping microduplication. Although available data are very limited, genomic and phenotype comparison of our and previously annotated patients suggested a potential clinical relevance for 16q24.2q24.3 microduplication with a variable and not (yet) recognizable phenotype predominantly affecting cognition. Comparing the cytogenomic data of available individuals allowed us to delineate the smallest region of overlap involving 14 genes. Accordingly, we propose ANKRD11, CDH15, and CTU2 as candidate genes for explaining the related neurodevelopmental manifestations shared by these patients.
    [Show full text]
  • E-Mutpath: Computational Modelling Reveals the Functional Landscape of Genetic Mutations Rewiring Interactome Networks
    bioRxiv preprint doi: https://doi.org/10.1101/2020.08.22.262386; this version posted August 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. e-MutPath: Computational modelling reveals the functional landscape of genetic mutations rewiring interactome networks Yongsheng Li1, Daniel J. McGrail1, Brandon Burgman2,3, S. Stephen Yi2,3,4,5 and Nidhi Sahni1,6,7,8,* 1Department oF Systems Biology, The University oF Texas MD Anderson Cancer Center, Houston, TX 77030, USA 2Department oF Oncology, Livestrong Cancer Institutes, Dell Medical School, The University oF Texas at Austin, Austin, TX 78712, USA 3Institute For Cellular and Molecular Biology (ICMB), The University oF Texas at Austin, Austin, TX 78712, USA 4Institute For Computational Engineering and Sciences (ICES), The University oF Texas at Austin, Austin, TX 78712, USA 5Department oF Biomedical Engineering, Cockrell School of Engineering, The University oF Texas at Austin, Austin, TX 78712, USA 6Department oF Epigenetics and Molecular Carcinogenesis, The University oF Texas MD Anderson Science Park, Smithville, TX 78957, USA 7Department oF BioinFormatics and Computational Biology, The University oF Texas MD Anderson Cancer Center, Houston, TX 77030, USA 8Program in Quantitative and Computational Biosciences (QCB), Baylor College oF Medicine, Houston, TX 77030, USA *To whom correspondence should be addressed. Nidhi Sahni. Tel: +1 512 2379506; Email: [email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.08.22.262386; this version posted August 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder.
    [Show full text]
  • BANP (1524CT337.6.32): Sc-517314
    SAN TA C RUZ BI OTEC HNOL OG Y, INC . BANP (1524CT337.6.32): sc-517314 BACKGROUND SOURCE BANP (BTG3 associated nuclear protein), also known as BEND1, SMARBP1 BANP (1524CT337.6.32) is a mouse monoclonal antibody raised against a or SMAR1, is a 519 amino acid protein that localizes to the nucleus and recombinant protein corresponding to amino acids 30-390 of BANP of human belongs to the BANP/SMAR1 family. Interacting with CDP and p53, BANP origin. functions to control V(D)J recombination during T-cell development, specifi - cally by binding to a scaffold/matrix DNA attachment region and repressing PRODUCT the enhancer function of TCR (T-cell receptor ). Additionally, BANP promotes β Each vial contains 100 µg IgG 1 kappa light chain in 1.0 ml of PBS with < 0.1% p53 serine phosphorylation, resulting in the subsequent nuclear accumulation sodium azide and 0.1% gelatin. of p53 and, ultimately, cell cycle arrest. BANP is down regulated in breast cancer cells, suggesting a role in tumor suppression. Three isoforms of BANP APPLICATIONS exist due to alternative splicing events. BANP (1524CT337.6.32) is recommended for detection of BANP of mouse, REFERENCES rat and human origin by Western Blotting (starting dilution 1:200, dilution range 1:100-1:1000) and immunoprecipitation [1-2 µg per 100-500 µg of total 1. Birot, A., Duret, L., Bartholin, L., Santalucia, B., Tigaud, I., Magaud, J. and protein (1 ml of cell lysate)]. Rouault, J. 2000. Identification and molecular analysis of BANP. Gene 253: 189-196. Suitable for use as control antibody for BANP siRNA (h): sc-72607, BANP siRNA (m): sc-72608, BANP shRNA Plasmid (h): sc-72607-SH, BANP shRNA 2.
    [Show full text]
  • Chromosomal Microarray Analysis in Turkish Patients with Unexplained Developmental Delay and Intellectual Developmental Disorders
    177 Arch Neuropsychitry 2020;57:177−191 RESEARCH ARTICLE https://doi.org/10.29399/npa.24890 Chromosomal Microarray Analysis in Turkish Patients with Unexplained Developmental Delay and Intellectual Developmental Disorders Hakan GÜRKAN1 , Emine İkbal ATLI1 , Engin ATLI1 , Leyla BOZATLI2 , Mengühan ARAZ ALTAY2 , Sinem YALÇINTEPE1 , Yasemin ÖZEN1 , Damla EKER1 , Çisem AKURUT1 , Selma DEMİR1 , Işık GÖRKER2 1Faculty of Medicine, Department of Medical Genetics, Edirne, Trakya University, Edirne, Turkey 2Faculty of Medicine, Department of Child and Adolescent Psychiatry, Trakya University, Edirne, Turkey ABSTRACT Introduction: Aneuploids, copy number variations (CNVs), and single in 39 (39/123=31.7%) patients. Twelve CNV variant of unknown nucleotide variants in specific genes are the main genetic causes of significance (VUS) (9.75%) patients and 7 CNV benign (5.69%) patients developmental delay (DD) and intellectual disability disorder (IDD). were reported. In 6 patients, one or more pathogenic CNVs were These genetic changes can be detected using chromosome analysis, determined. Therefore, the diagnostic efficiency of CMA was found to chromosomal microarray (CMA), and next-generation DNA sequencing be 31.7% (39/123). techniques. Therefore; In this study, we aimed to investigate the Conclusion: Today, genetic analysis is still not part of the routine in the importance of CMA in determining the genomic etiology of unexplained evaluation of IDD patients who present to psychiatry clinics. A genetic DD and IDD in 123 patients. diagnosis from CMA can eliminate genetic question marks and thus Method: For 123 patients, chromosome analysis, DNA fragment analysis alter the clinical management of patients. Approximately one-third and microarray were performed. Conventional G-band karyotype of the positive CMA findings are clinically intervenable.
    [Show full text]
  • Identification and Molecular Analysis of BANP
    Gene 253 (2000) 189–196 www.elsevier.com/locate/gene Identification and molecular analysis of BANP Anne-Marie Birot a, Laurent Duret c, Laurent Bartholin a,Be´ne´dicte Santalucia b, Isabelle Tigaud b, Jean-Pierre Magaud a,b, Jean-Pierre Rouault a,* a Unite´ INSERM U453, aYlie´e au CNRS, Centre Le´on Be´rard, Batiment Le Cheney, 28 rue Lae¨nnec, 69373 Lyon Ce´dex 08, France b Service de cytoge´ne´tique, Hopital Edouard Herriot, Pavillon E, Lyon, France c Laboratoire BGBP-UMR 5558, UCLB, Villeurbanne, France Received 24 March 2000; received in revised form 26 May 2000; accepted 30 May 2000 Received by A. Bernardi Abstract BTG3 belongs to a family of structurally related genes whose biochemical functions remain elusive. In order to investigate the mechanism underlying BTG3-mediated functions, we tried to identify BTG3 potential partners. The use of the yeast ‘two-hybrid system’, with BTG3 as bait, enabled us to isolate BANP (BTG3 Associated Nuclear Protein). Other commonly used protein- binding assays did not confirm this yeast interaction. However, BANP had never been described before, and this prompted us to further characterise this gene. In this paper, we present data on its molecular organization in mouse, then we speculate on the nature of this nuclear protein, and finally we localise BANP on the human chromosome 16q24 subregion; we discuss the fact that frequent loss of heterozygosity within this region has been observed in diVerent tumours. © 2000 Elsevier Science B.V. All rights reserved. Keywords: ANA; BTG; BTG3; rBTG3; 16q24 1. Introduction an altered G2/M block as compared with naive cells when they are treated with genotoxic agents (Rouault The mouse BTG3 gene (Gue´henneux et al., 1997) et al., 1996).
    [Show full text]
  • Emerging Roles of Circrna in Formation and Progression of Cancer
    Journal of Cancer 2019, Vol. 10 5015 Ivyspring International Publisher Journal of Cancer 2019; 10(21): 5015-5021. doi: 10.7150/jca.30828 Review Emerging roles of circRNA in formation and progression of cancer Yuting Yin*, Jiali Long*, Qinglian He, Yuling Li, Yanqiu Liao, Peishan He, Wei Zhu Department of Pathology, Guangdong Medical University, Dongguan 523808, Guangdong Province, China *Contributed equally Corresponding author: Wei Zhu, MD, Department of Pathology, Guangdong Medical University, No.1 Xincheng Road, Dongguan 523808, Guangdong Province, China. 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: 2018.10.21; Accepted: 2019.08.05; Published: 2019.08.28 Abstract Circular RNAs (circRNAs) are recently discovered as a special novel type of endogenous noncoding RNAs (ncRNAs), which form a covalently closed continuous loop and are highly represented in the eukaryotic transcriptome. Recent research revealed that circRNAs can function as microRNA (miRNA) sponges, regulators of splicing and transcription, as well as interact with RNA-binding proteins (RBPs). In this review, not only the function and mechanism, but also the experimental methods of circRNA are summarized. The summary of the current state of circRNA will help us in the discovery of novel biomarkers, the therapeutic targets and their potential significance in diagnosis and treatment of diseases. CircRNAs might play important roles in cancers especially in hepatocellular carcinoma, gastric carcinoma and colorectal cancer as well as serving as diagnostic or predictive biomarkers of some diseases and providing new treatments of diseases.
    [Show full text]
  • Transcriptional Regulators Are Upregulated in the Substantia Nigra
    Journal of Emerging Investigators Transcriptional Regulators are Upregulated in the Substantia Nigra of Parkinson’s Disease Patients Marianne Cowherd1 and Inhan Lee2 1Community High School, Ann Arbor, MI 2miRcore, Ann Arbor, MI Summary neurological conditions is an established practice (3). Parkinson’s disease (PD) affects approximately 10 Significant gene expression dysregulation in the SN and million people worldwide with tremors, bradykinesia, in the striatum has been described, particularly decreased apathy, memory loss, and language issues. Though such expression in PD synapses. Protein degradation has symptoms are due to the loss of the substantia nigra (SN) been found to be upregulated (4). Mutations in SNCA brain region, the ultimate causes and complete pathology are unknown. To understand the global gene expression (5), LRRK2 (6), and GBA (6) have also been identified changes in SN, microarray expression data from the SN as familial markers of PD. SNCA encodes alpha- tissue of 9 controls and 16 PD patients were compared, synuclein, a protein found in presynaptic terminals that and significantly upregulated and downregulated may regulate vesicle presence and dopamine release. genes were identified. Among the upregulated genes, Eighteen SNCA mutations have been associated with a network of 33 interacting genes centered around the PD and, although the exact pathogenic mechanism is cAMP-response element binding protein (CREBBP) was not confirmed, mutated alpha-synuclein is the major found. The downstream effects of increased CREBBP- component of protein aggregates, called Lewy bodies, related transcription and the resulting protein levels that are often found in PD brains and may contribute may result in PD symptoms, making CREBBP a potential therapeutic target due to its central role in the interactive to cell death.
    [Show full text]
  • The Hormone-Bound Vitamin D Receptor Regulates Turnover of Target
    The hormone-bound vitamin D receptor regulates turnover of target proteins of the SCFFBW7 E3 ligase By Reyhaneh Salehi Tabar Department of Experimental Medicine McGill University Montreal, QC, Canada April 2016 A thesis submitted to McGill University in partial fulfillment of the requirements of the degree of Doctor of Philosophy © Reyhaneh Salehi Tabar 1 Table of Contents Abbreviations ................................................................................................................................................ 7 Abstract ....................................................................................................................................................... 10 Rèsumè ....................................................................................................................................................... 13 Acknowledgements ..................................................................................................................................... 16 Preface ........................................................................................................................................................ 17 Contribution of authors .............................................................................................................................. 18 Chapter 1-Literature review........................................................................................................................ 20 1.1. General introduction and overview of thesis ............................................................................
    [Show full text]
  • The Proteins of Keratoconus: a Literature Review Exploring Their Contribution to the Pathophysiology of the Disease
    Adv Ther (2019) 36:2205–2222 https://doi.org/10.1007/s12325-019-01026-0 REVIEW The Proteins of Keratoconus: a Literature Review Exploring Their Contribution to the Pathophysiology of the Disease Eleftherios Loukovitis . Nikolaos Kozeis . Zisis Gatzioufas . Athina Kozei . Eleni Tsotridou . Maria Stoila . Spyros Koronis . Konstantinos Sfakianakis . Paris Tranos . Miltiadis Balidis . Zacharias Zachariadis . Dimitrios G. Mikropoulos . George Anogeianakis . Andreas Katsanos . Anastasios G. Konstas Received: June 11, 2019 / Published online: July 30, 2019 Ó The Author(s) 2019 ABSTRACT abnormalities primarily relate to the weakening of the corneal collagen. Their understanding is Introduction: Keratoconus (KC) is a complex, crucial and could contribute to effective man- genetically heterogeneous multifactorial agement of the disease, such as with the aid of degenerative disorder characterized by corneal corneal cross-linking (CXL). The present article ectasia and thinning. Its incidence is approxi- critically reviews the proteins involved in the mately 1/2000–1/50,000 in the general popula- pathophysiology of KC, with particular tion. KC is associated with moderate to high emphasis on the characteristics of collagen that myopia and irregular astigmatism, resulting in pertain to CXL. severe visual impairment. KC structural Methods: PubMed, MEDLINE, Google Scholar and GeneCards databases were screened for rel- evant articles published in English between January 2006 and June 2018. Keyword combi- Enhanced Digital Features To view enhanced digital nations of the words ‘‘keratoconus,’’ ‘‘risk features for this article go to https://doi.org/10.6084/ m9.figshare.8427200. E. Loukovitis K. Sfakianakis Hellenic Army Medical Corps, Thessaloniki, Greece Division of Surgical Anatomy, Laboratory of Anatomy, Medical School, Democritus University of E.
    [Show full text]
  • Nucleus Accumbens-Associated Protein 1 Binds DNA Directly Through the BEN Domain in a Sequence-Specific Manner
    biomedicines Article Nucleus Accumbens-Associated Protein 1 Binds DNA Directly through the BEN Domain in a Sequence-Specific Manner Naomi Nakayama 1,2, Gyosuke Sakashita 1, Takashi Nagata 3,4 , Naohiro Kobayashi 5, Hisashi Yoshida 6, Sam-Yong Park 6, Yuko Nariai 1, Hiroaki Kato 1, Eiji Obayashi 1, Kentaro Nakayama 7, Satoru Kyo 7 and Takeshi Urano 1,* 1 Department of Biochemistry, Shimane University School of Medicine, Izumo, Shimane 693-8501, Japan; [email protected] (N.N.); [email protected] (G.S.); [email protected] (Y.N.); [email protected] (H.K.); [email protected] (E.O.) 2 Department of Health and Nutrition, The University of Shimane, Izumo, Shimane 693-8550, Japan 3 Institute of Advanced Energy, Kyoto University, Kyoto 606-8501, Japan; [email protected] 4 Graduate School of Energy Science, Kyoto University, Kyoto 606-8501, Japan 5 Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan; [email protected] 6 Protein Design Laboratory, Graduate School of Medical Life Science, Yokohama City University, Yokohama, Kanagawa 230-0045, Japan; [email protected] (H.Y.); [email protected] (S.-Y.P.) 7 Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo, Shimane 693-8501, Japan; [email protected] (K.N.); [email protected] (S.K.) * Correspondence: [email protected]; Tel.: +81-853-20-2126 Received: 2 December 2020; Accepted: 10 December 2020; Published: 14 December 2020 Abstract: Nucleus accumbens-associated protein 1 (NAC1) is a nuclear protein that harbors an amino-terminal BTB domain and a carboxyl-terminal BEN domain.
    [Show full text]
  • Tools and Technologies to Characterize Isoforms at Proteome-Scale
    Tools and technologies to characterize isoforms at proteome-scale Gloria Sheynkman Marc Vidal Laboratory Center for Cancer Systems Biology, Dana Faber Cancer Institute Department of Genetics, Harvard University SMRTLeiden May 2nd, 2017 CCSB CENTER FOR CANCER SYSTEMS BIOLOGY Gene numbers Number 20K of genes Complexity Ensembl Dec 2015 release Isoform numbers 100K Number of Numbersplice of formsisoforms Number 20K of genes Complexity Ensembl Dec 2015 release Combinations of splice sites produce diverse protein isoforms. Tropomyosin Alpha-1 Chain chr15:63,334,785-63,364,028 MCF-7 Cells A G A AA AAA canonical alternative casette constitutive nucleotide retained alternative alternative A A lncRNA canonical A A A promoter promoter exon exons polymorphism intron donor 3’ end polyadenylation site (5’ end) AAA A A A AAA A A A AAA A A A A AA A A A AA A A A AA A A A AA A A AAA A A A AAA A A A AAA A A A AAA A A A A AA A A The proteoform hypothesis ~100K isoforms ~1 million proteoforms Smith & Kelleher Nat Methods 2013 Splicing regulation and disease •splicing is pervasive, inherent to encoded products of the genome •splicing is highly regulated in space and time •high tissue- and developmental- specificity •“splice code” •splicing is dysregulated in many diseases, including cancer •estimates of 50% all disease variants affect splicing •splice-modulating therapies (e.g. antisense oligos) Wang et al Nature Review Genetics (2007), 6 Isoform function? 100K Number of Numbersplice of formsisoforms Number 20K of genes Complexity Ensembl Dec 2015 release Isoforms and functional divergence In vivo functions Identical “Isoforms” Different “Alloforms” Opposite “Antiforms” Examples of functionally divergent isoforms Alloforms Antiforms Bcl-X anti-apoptotic Bcl-X pro-apoptotic Christofk et al Nature 2008 Schwerk et al Mol Cell 2005 Divergent functional capabilities described in literature Isoforms for a few hundred genes Physical interactions Cellular localization Enzymatic activities Stability ….
    [Show full text]