Using Hidden Markov Models to Investigate G- Quadruplex Motifs in Genomic Sequences
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The N-Cadherin Interactome in Primary Cardiomyocytes As Defined Using Quantitative Proximity Proteomics Yang Li1,*, Chelsea D
© 2019. Published by The Company of Biologists Ltd | Journal of Cell Science (2019) 132, jcs221606. doi:10.1242/jcs.221606 TOOLS AND RESOURCES The N-cadherin interactome in primary cardiomyocytes as defined using quantitative proximity proteomics Yang Li1,*, Chelsea D. Merkel1,*, Xuemei Zeng2, Jonathon A. Heier1, Pamela S. Cantrell2, Mai Sun2, Donna B. Stolz1, Simon C. Watkins1, Nathan A. Yates1,2,3 and Adam V. Kwiatkowski1,‡ ABSTRACT requires multiple adhesion, cytoskeletal and signaling proteins, The junctional complexes that couple cardiomyocytes must transmit and mutations in these proteins can cause cardiomyopathies (Ehler, the mechanical forces of contraction while maintaining adhesive 2018). However, the molecular composition of ICD junctional homeostasis. The adherens junction (AJ) connects the actomyosin complexes remains poorly defined. – networks of neighboring cardiomyocytes and is required for proper The core of the AJ is the cadherin catenin complex (Halbleib and heart function. Yet little is known about the molecular composition of the Nelson, 2006; Ratheesh and Yap, 2012). Classical cadherins are cardiomyocyte AJ or how it is organized to function under mechanical single-pass transmembrane proteins with an extracellular domain that load. Here, we define the architecture, dynamics and proteome of mediates calcium-dependent homotypic interactions. The adhesive the cardiomyocyte AJ. Mouse neonatal cardiomyocytes assemble properties of classical cadherins are driven by the recruitment of stable AJs along intercellular contacts with organizational and cytosolic catenin proteins to the cadherin tail, with p120-catenin β structural hallmarks similar to mature contacts. We combine (CTNND1) binding to the juxta-membrane domain and -catenin β quantitative mass spectrometry with proximity labeling to identify the (CTNNB1) binding to the distal part of the tail. -
Ahnaks Are a Class of Giant Propeller-Like Proteins That Associate with Calcium Channel Proteins of Cardiomyocytes and Other Cells
The AHNAKs are a class of giant propeller-like proteins that associate with calcium channel proteins of cardiomyocytes and other cells Akihiko Komuro*, Yutaka Masuda*, Koichi Kobayashi, Roger Babbitt, Murat Gunel, Richard A. Flavell, and Vincent T. Marchesi† Departments of Pathology and Immunobiology, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, CT 06510 Contributed by Vincent T. Marchesi, December 31, 2003 To explore the function of the giant AHNAK molecule, first de- mechanisms, one operating at the cell surface in collaboration with scribed in 1992 [Shtivelman, E., Cohen, F. E. & Bishop, J. M. (1992) calcium channels, and the second, PLC activation, which is a process Proc. Natl. Acad. Sci. USA 89, 5472–5476], we created AHNAK null that could potentially take place at multiple points throughout the mice by homologous recombination. Homozygous knockouts cell. showed no obvious phenotype, but revealed instead a second The arrangement of channel proteins at the cell surface is AHNAK-like molecule, provisionally designated AHNAK2. Like the believed to be controlled by multidomain polypeptides known as original AHNAK, AHNAK2 is a 600-kDa protein composed of a large scaffolding proteins that link together activated channels at specific number of highly conserved repeat segments. Structural predic- points on the membrane surface. Scaffolding proteins also coordi- tions suggest that the repeat segments of both AHNAKs may have nate the activities of multienzyme complexes by physically linking as their basic framework a series of linked, antiparallel -strands them together, and as in the case with AHNAK, they are often similar to those found in -propeller proteins. -
Identification of Cis-Regulatory Sequence
Worsley-Hunt et al. Genome Medicine 2011, 3:65 http://genomemedicine.com/content/3/9/65 REVIEW Identication of cis-regulatory sequence variations in individual genome sequences Rebecca Worsley-Hunt1,2, Virginie Bernard1 and Wyeth W Wasserman1* Abstract for the appropriate patterning or magnitude of gene expression. Similarly, mutations can disrupt other sequence- Functional contributions of cis-regulatory sequence specific regulatory controls, such as elements regulating variations to human genetic disease are numerous. For RNA splicing or stability. Although much emphasis in the instance, disrupting variations in a HNF4A transcription age of exome sequencing has been placed on variation factor binding site upstream of the Factor IX gene within protein-encoding sequences, it is apparent that contributes causally to hemophilia B Leyden. Although regulatory sequence disruptions will become a key focus clinical genome sequence analysis currently focuses as full genome sequences become widely accessible for on the identication of protein-altering variation, the medical genetics research. impact of cis-regulatory mutations can be similarly e emerging collection of cis-regulatory variations strong. New technologies are now enabling genome that cause human disease or altered phenotype is grow- sequencing beyond exomes, revealing variation across ing [2-4]. Reports identify cis-acting, expression-altering the non-coding 98% of the genome responsible for mutations observed within introns, far upstream of developmental and physiological patterns of gene genes, at splicing sites or within microRNA target sites. activity. The capacity to identify causal regulatory For example, cis-regulatory mutations have roles in hemo- mutations is improving, but predicting functional philia, Gilbert’s syndrome, Bernard-Soulier syndrome, changes in regulatory DNA sequences remains a great irritable bowel syndrome, beta-thalassemia, cholesterol challenge. -
Transcriptome-Wide Profiling of Cerebral Cavernous Malformations
www.nature.com/scientificreports OPEN Transcriptome-wide Profling of Cerebral Cavernous Malformations Patients Reveal Important Long noncoding RNA molecular signatures Santhilal Subhash 2,8, Norman Kalmbach3, Florian Wegner4, Susanne Petri4, Torsten Glomb5, Oliver Dittrich-Breiholz5, Caiquan Huang1, Kiran Kumar Bali6, Wolfram S. Kunz7, Amir Samii1, Helmut Bertalanfy1, Chandrasekhar Kanduri2* & Souvik Kar1,8* Cerebral cavernous malformations (CCMs) are low-fow vascular malformations in the brain associated with recurrent hemorrhage and seizures. The current treatment of CCMs relies solely on surgical intervention. Henceforth, alternative non-invasive therapies are urgently needed to help prevent subsequent hemorrhagic episodes. Long non-coding RNAs (lncRNAs) belong to the class of non-coding RNAs and are known to regulate gene transcription and involved in chromatin remodeling via various mechanism. Despite accumulating evidence demonstrating the role of lncRNAs in cerebrovascular disorders, their identifcation in CCMs pathology remains unknown. The objective of the current study was to identify lncRNAs associated with CCMs pathogenesis using patient cohorts having 10 CCM patients and 4 controls from brain. Executing next generation sequencing, we performed whole transcriptome sequencing (RNA-seq) analysis and identifed 1,967 lncRNAs and 4,928 protein coding genes (PCGs) to be diferentially expressed in CCMs patients. Among these, we selected top 6 diferentially expressed lncRNAs each having signifcant correlative expression with more than 100 diferentially expressed PCGs. The diferential expression status of the top lncRNAs, SMIM25 and LBX2-AS1 in CCMs was further confrmed by qRT-PCR analysis. Additionally, gene set enrichment analysis of correlated PCGs revealed critical pathways related to vascular signaling and important biological processes relevant to CCMs pathophysiology. -
Mir-17-92 Fine-Tunes MYC Expression and Function to Ensure
ARTICLE Received 31 Mar 2015 | Accepted 22 Sep 2015 | Published 10 Nov 2015 DOI: 10.1038/ncomms9725 OPEN miR-17-92 fine-tunes MYC expression and function to ensure optimal B cell lymphoma growth Marija Mihailovich1, Michael Bremang1, Valeria Spadotto1, Daniele Musiani1, Elena Vitale1, Gabriele Varano2,w, Federico Zambelli3, Francesco M. Mancuso1,w, David A. Cairns1,w, Giulio Pavesi3, Stefano Casola2 & Tiziana Bonaldi1 The synergism between c-MYC and miR-17-19b, a truncated version of the miR-17-92 cluster, is well-documented during tumor initiation. However, little is known about miR-17-19b function in established cancers. Here we investigate the role of miR-17-19b in c-MYC-driven lymphomas by integrating SILAC-based quantitative proteomics, transcriptomics and 30 untranslated region (UTR) analysis upon miR-17-19b overexpression. We identify over one hundred miR-17-19b targets, of which 40% are co-regulated by c-MYC. Downregulation of a new miR-17/20 target, checkpoint kinase 2 (Chek2), increases the recruitment of HuR to c- MYC transcripts, resulting in the inhibition of c-MYC translation and thus interfering with in vivo tumor growth. Hence, in established lymphomas, miR-17-19b fine-tunes c-MYC activity through a tight control of its function and expression, ultimately ensuring cancer cell homeostasis. Our data highlight the plasticity of miRNA function, reflecting changes in the mRNA landscape and 30 UTR shortening at different stages of tumorigenesis. 1 Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, Milan 20139, Italy. 2 Units of Genetics of B cells and lymphomas, IFOM, FIRC Institute of Molecular Oncology Foundation, Milan 20139, Italy. -
CCM1 and CCM2 Variants in Patients with Cerebral Cavernous
www.nature.com/scientificreports OPEN CCM1 and CCM2 variants in patients with cerebral cavernous malformation in an ethnically Received: 19 January 2018 Accepted: 11 July 2019 Chinese population in Taiwan Published: xx xx xxxx Chun-Wei Chang 1, Peng-Wei Hsu2,3, Kuo-Chen Wei2,3, Chia-Wen Chang1, Hon-Chung Fung1, Mo-Song Hsih1, Wen-Chuin Hsu1,3, Long-Sun Ro1,3, Chen-Nen Chang2,4, Jiun-Jie Wang5,6, Yih-Ru Wu1,3 & Sien-Tsong Chen1 Cerebral cavernous malformation (CCM) is a vascular malformation characterized by clustered enlarged capillary-like channels in the central nervous system. The genes harboring variants in patients with CCM include CCM1/Krev interaction trapped-1, CCM2/MGC4607, and CCM3/programmed cell death protein 10. We aimed to identify pathogenic variants in an ethnic Chinese population in Taiwan. We recruited 95 patients with multiple CCMs or a single lesion with a relevant family history. Sanger sequencing was performed for 41 patients. Variants were identifed using sequence alignment tools, and the clinical signifcance of these variants was determined using American College of Medical Genetics and Genomics standards and guidelines. Several pathogenic variants were found in six patients, including three unrelated patients and three afected members of one family. Two novel pathogenic variants leading to early truncation comprised a deletion variant in exon 18 of CCM1 (c.1846delA; p.Glu617LysfsTer44) and an insertion variant in exon 4 of CCM2 (c.401_402insGCCC; p.Ile136AlafsTer4). One novel pathogenic splice site variant was c.485 + 1G > C at the beginning of intron 8 of CCM1. In this study, we identifed novel variants related to CCM in an ethnically Chinese population in Taiwan. -
Overexpression of RNF38 Facilitates TGF-Β Signaling by Ubiquitinating
Peng et al. Journal of Experimental & Clinical Cancer Research (2019) 38:113 https://doi.org/10.1186/s13046-019-1113-3 RESEARCH Open Access Overexpression of RNF38 facilitates TGF-β signaling by Ubiquitinating and degrading AHNAK in hepatocellular carcinoma Rui Peng1,2†, Peng-Fei Zhang1,3†, Xuan Yang1†, Chuan-Yuan Wei1†, Xiao-Yong Huang1, Jia-Bin Cai1, Jia-Cheng Lu1, Chao Gao1, Hai-Xiang Sun1, Qiang Gao1, Dou-Sheng Bai2, Guo-Ming Shi1*, Ai-Wu Ke1* and Jia Fan1,4* Abstract Background: RING finger protein 38 (RNF38), a member of the RNF protein family, has just emerged as a vital driver of cancer progression. However, the oncogenic mechanisms of RNF38 remain unexplored. Methods: Using frozen tumor tissue and tissue microarray from hepatocellular carcinoma (HCC) patients, we tried to probe the expression of RNF38 in HCC and its clinical value. Then the biological functions of RNF38 were analyzed in vivo and vitro. Stable isotope labeling with amino acids (SILAC) in cell culture and co-immunoprecipitation proteomic analyses were combined to reveal the potential mechanism of RNF38 in HCC progression. Results: We report that RNF38 expression was markedly higher in HCC tissues than in peritumor tissues. Correspondingly, RNF38 overexpression promoted the HCC cell migration and invasion and inhibited apoptosis both in vitro and in vivo. And elevated RNF38 expression induced HCC cell epithelial-mesenchymal transition by facilitating transforming growth factor-β (TGF-β) signaling via ubiquitinating and degrading neuroblast differentiation-associated protein (AHNAK), a well-established inhibitor of TGF-β signaling. Furthermore, AHNAK interference restored the HCC cell invasion and metastasis deprived by RNF38 downregulation. -
CD29 Identifies IFN-Γ–Producing Human CD8+ T Cells with an Increased Cytotoxic Potential
+ CD29 identifies IFN-γ–producing human CD8 T cells with an increased cytotoxic potential Benoît P. Nicoleta,b, Aurélie Guislaina,b, Floris P. J. van Alphenc, Raquel Gomez-Eerlandd, Ton N. M. Schumacherd, Maartje van den Biggelaarc,e, and Monika C. Wolkersa,b,1 aDepartment of Hematopoiesis, Sanquin Research, 1066 CX Amsterdam, The Netherlands; bLandsteiner Laboratory, Oncode Institute, Amsterdam University Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; cDepartment of Research Facilities, Sanquin Research, 1066 CX Amsterdam, The Netherlands; dDivision of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; and eDepartment of Molecular and Cellular Haemostasis, Sanquin Research, 1066 CX Amsterdam, The Netherlands Edited by Anjana Rao, La Jolla Institute for Allergy and Immunology, La Jolla, CA, and approved February 12, 2020 (received for review August 12, 2019) Cytotoxic CD8+ T cells can effectively kill target cells by producing therefore developed a protocol that allowed for efficient iso- cytokines, chemokines, and granzymes. Expression of these effector lation of RNA and protein from fluorescence-activated cell molecules is however highly divergent, and tools that identify and sorting (FACS)-sorted fixed T cells after intracellular cytokine + preselect CD8 T cells with a cytotoxic expression profile are lacking. staining. With this top-down approach, we performed an un- + Human CD8 T cells can be divided into IFN-γ– and IL-2–producing biased RNA-sequencing (RNA-seq) and mass spectrometry cells. Unbiased transcriptomics and proteomics analysis on cytokine- γ– – + + (MS) analyses on IFN- and IL-2 producing primary human producing fixed CD8 T cells revealed that IL-2 cells produce helper + + + CD8 Tcells. -
Cerebral Cavernous Malformations: from Genes to Proteins to Disease
See the corresponding editorial in this issue, pp 119–121. J Neurosurg 116:122–132, 2012 Cerebral cavernous malformations: from genes to proteins to disease Clinical article DANIEL D. CAVALCANTI, M.D., M. YASHAR S. KALANI, M.D., PH.D., NIKOLAY L. MARTIROSYAN, M.D., JUSTIN EALES, B.S., ROBERT F. SPETZLER, M.D., AND MARK C. PREUL, M.D. Division of Neurological Surgery, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, Arizona Over the past half century molecular biology has led to great advances in our understanding of angio- and vas- culogenesis and in the treatment of malformations resulting from these processes gone awry. Given their sporadic and familial distribution, their developmental and pathological link to capillary telangiectasias, and their observed chromosomal abnormalities, cerebral cavernous malformations (CCMs) are regarded as akin to cancerous growths. Although the exact pathological mechanisms involved in the formation of CCMs are still not well understood, the identification of 3 genetic loci has begun to shed light on key developmental pathways involved in CCM pathogen- esis. Cavernous malformations can occur sporadically or in an autosomal dominant fashion. Familial forms of CCMs have been attributed to mutations at 3 different loci implicated in regulating important processes such as proliferation and differentiation of angiogenic precursors and members of the apoptotic machinery. These processes are important for the generation, maintenance, and pruning of every vessel in the body. In this review the authors highlight the lat- est discoveries pertaining to the molecular genetics of CCMs, highlighting potential new therapeutic targets for the treatment of these lesions. -
A Focus on Genetic Features of Cerebral Cavernous Malformations and Brain Arteriovenous Malformations Pathogenesis
Neurological Sciences (2019) 40:243–251 https://doi.org/10.1007/s10072-018-3674-x REVIEW ARTICLE Vis-à-vis: a focus on genetic features of cerebral cavernous malformations and brain arteriovenous malformations pathogenesis Concetta Scimone1,2 & Luigi Donato 1,2 & Silvia Marino3 & Concetta Alafaci1 & Rosalia D’Angelo1 & Antonina Sidoti1,2 Received: 7 September 2018 /Accepted: 1 December 2018 /Published online: 6 December 2018 # Fondazione Società Italiana di Neurologia 2018 Abstract Cerebrovascular malformations include a wide range of blood vessel disorders affecting brain vasculature. Neuroimaging differential diagnosis can result unspecific due to similar phenotypes of lesions and their deep locali- zation. Next-generation sequencing (NGS) platforms simultaneously analyze several hundreds of genes and can be applied for molecular distinction of different phenotypes within the same disorder’s macro-area. We discuss about the main criticisms regarding molecular bases of cerebral cavernous malformations (CCM) and brain arteriovenous malformations (AVM), highlighting both common pathogenic aspects and genetic differences leading to lesion devel- opment. Many recent studies performed on human CCM and AVM tissues aim to detect genetic markers to better understand molecular bases and pathogenic mechanism, particularly for sporadic cases. Several genes involved in angiogenesis show different expression patterns between CCM and AVM, and these could represent a valid starting point to project a NGS panel to apply for differential cerebrovascular malformation diagnosis. Keywords Cerebral cavernous malformations . Arteriovenous malformations . Genetics . Differential molecular diagnosis Introduction #116860) and arteriovenous malformations (AVM, OMIM #108010) are the most frequent, affecting more Cerebrovascular malformations include a wide spectrum than 3% of the population [1]. Venous developmental of intracranial blood vessel disorders, involving arterial anomalies (VDAs) are rare conditions usually associated wall, capillary bed, and venous and lymphatic systems. -
A Genome-Wide Association Study of Idiopathic Dilated Cardiomyopathy in African Americans
Journal of Personalized Medicine Article A Genome-Wide Association Study of Idiopathic Dilated Cardiomyopathy in African Americans Huichun Xu 1,* ID , Gerald W. Dorn II 2, Amol Shetty 3, Ankita Parihar 1, Tushar Dave 1, Shawn W. Robinson 4, Stephen S. Gottlieb 4 ID , Mark P. Donahue 5, Gordon F. Tomaselli 6, William E. Kraus 5,7 ID , Braxton D. Mitchell 1,8 and Stephen B. Liggett 9,* 1 Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA; [email protected] (A.P.); [email protected] (T.D.); [email protected] (B.D.M.) 2 Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; [email protected] 3 Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA; [email protected] 4 Division of Cardiovascular Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA; [email protected] (S.W.R.); [email protected] (S.S.G.) 5 Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC 27708, USA; [email protected] (M.P.D.); [email protected] (W.E.K.) 6 Department of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD 21218, USA; [email protected] 7 Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC 27701, USA 8 Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration -
Global Analysis of O-Glcnac Glycoproteins in Activated Human T Cells Peder J
Global Analysis of O-GlcNAc Glycoproteins in Activated Human T Cells Peder J. Lund, Joshua E. Elias and Mark M. Davis This information is current as J Immunol 2016; 197:3086-3098; Prepublished online 21 of October 2, 2021. September 2016; doi: 10.4049/jimmunol.1502031 http://www.jimmunol.org/content/197/8/3086 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2016/09/20/jimmunol.150203 Material 1.DCSupplemental References This article cites 89 articles, 32 of which you can access for free at: http://www.jimmunol.org/content/197/8/3086.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on October 2, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Author Choice Freely available online through The Journal of Immunology Author Choice option Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Global Analysis of O-GlcNAc Glycoproteins in Activated Human T Cells Peder J.