Correlation Profiling of Brain Sub-Cellular Proteomes Reveals Co
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Characterization of BRCA1-Deficient Premalignant Tissues and Cancers Identifies Plekha5 As a Tumor Metastasis Suppressor
ARTICLE https://doi.org/10.1038/s41467-020-18637-9 OPEN Characterization of BRCA1-deficient premalignant tissues and cancers identifies Plekha5 as a tumor metastasis suppressor Jianlin Liu1,2, Ragini Adhav1,2, Kai Miao1,2, Sek Man Su1,2, Lihua Mo1,2, Un In Chan1,2, Xin Zhang1,2, Jun Xu1,2, Jianjie Li1,2, Xiaodong Shu1,2, Jianming Zeng 1,2, Xu Zhang1,2, Xueying Lyu1,2, Lakhansing Pardeshi1,3, ✉ ✉ Kaeling Tan1,3, Heng Sun1,2, Koon Ho Wong 1,3, Chuxia Deng 1,2 & Xiaoling Xu 1,2 1234567890():,; Single-cell whole-exome sequencing (scWES) is a powerful approach for deciphering intra- tumor heterogeneity and identifying cancer drivers. So far, however, simultaneous analysis of single nucleotide variants (SNVs) and copy number variations (CNVs) of a single cell has been challenging. By analyzing SNVs and CNVs simultaneously in bulk and single cells of premalignant tissues and tumors from mouse and human BRCA1-associated breast cancers, we discover an evolution process through which the tumors initiate from cells with SNVs affecting driver genes in the premalignant stage and malignantly progress later via CNVs acquired in chromosome regions with cancer driver genes. These events occur randomly and hit many putative cancer drivers besides p53 to generate unique genetic and pathological features for each tumor. Upon this, we finally identify a tumor metastasis suppressor Plekha5, whose deficiency promotes cancer metastasis to the liver and/or lung. 1 Cancer Centre, Faculty of Health Sciences, University of Macau, Macau, SAR, China. 2 Centre for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau, SAR, China. -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase -
Mutation of Plekha7 Attenuates Salt-Sensitive Hypertension in the Rat
Mutation of Plekha7 attenuates salt-sensitive hypertension in the rat Bradley T. Endresa,b, Jessica R. C. Priestleya, Oleg Palygina, Michael J. Flistera,b, Matthew J. Hoffmana, Brian D. Weinberga, Michael Grzybowskia,b, Julian H. Lombarda, Alexander Staruschenkoa, Carol Morenoa,b, Howard J. Jacoba,b,c, and Aron M. Geurtsa,b,d,1 Departments of aPhysiology and cPediatrics, bHuman and Molecular Genetics Center, and dCardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226 Edited by Richard P. Lifton, Yale University School of Medicine, New Haven, CT, and approved July 23, 2014 (received for review June 24, 2014) PLEKHA7 (pleckstrin homology domain containing family A mem- hypertension and renal injury by selective ablation of adaptive im- em1Mcwi em1Mcwi ber 7) has been found in multiple studies as a candidate gene for mune cells in the SS-Rag1 and SS-Cd247 knockout human hypertension, yet functional data supporting this associa- rats (16, 17) and reduced hypertension and renal injury in the em1Mcwi tion are lacking. We investigated the contribution of this gene SS-Ncf2 (p67phox) null model exhibiting reduced medul- to the pathogenesis of salt-sensitive hypertension by mutating lary oxidative stress (18). Additionally, we have recently demon- Plekha7 in the Dahl salt-sensitive (SS/JrHsdMcwi) rat using zinc- strated multiple genes at a single hypertension GWAS-nominated finger nuclease technology. After four weeks on an 8% NaCl diet, locus (Agtrap-Plod1 locus) can have additive or subtractive effects homozygous mutant rats had lower mean arterial (149 ± 9 mmHg on blood pressure and renal function when mutated in the SS rat vs. -
Autism-Associated Mir-873 Regulates ARID1B, SHANK3 and NRXN2
Lu et al. Translational Psychiatry (2020) 10:418 https://doi.org/10.1038/s41398-020-01106-8 Translational Psychiatry ARTICLE Open Access Autism-associated miR-873 regulates ARID1B, SHANK3 and NRXN2 involved in neurodevelopment Jing Lu 1, Yan Zhu 1, Sarah Williams2, Michelle Watts 3,MaryA.Tonta1, Harold A. Coleman1, Helena C. Parkington1 and Charles Claudianos 1,4 Abstract Autism spectrum disorders (ASD) are highly heritable neurodevelopmental disorders with significant genetic heterogeneity. Noncoding microRNAs (miRNAs) are recognised as playing key roles in development of ASD albeit the function of these regulatory genes remains unclear. We previously conducted whole-exome sequencing of Australian families with ASD and identified four novel single nucleotide variations in mature miRNA sequences. A pull-down transcriptome analysis using transfected SH-SY5Y cells proposed a mechanistic model to examine changes in binding affinity associated with a unique mutation found in the conserved ‘seed’ region of miR-873-5p (rs777143952: T > A). Results suggested several ASD-risk genes were differentially targeted by wild-type and mutant miR-873 variants. In the current study, a dual-luciferase reporter assay confirmed miR-873 variants have a 20-30% inhibition/dysregulation effect on candidate autism risk genes ARID1B, SHANK3 and NRXN2 and also confirmed the affected expression with qPCR. In vitro mouse hippocampal neurons transfected with mutant miR-873 showed less morphological complexity and enhanced sodium currents and excitatory neurotransmission compared to cells transfected with wild-type miR- 873. A second in vitro study showed CRISPR/Cas9 miR-873 disrupted SH-SY5Y neuroblastoma cells acquired a neuronal-like morphology and increased expression of ASD important genes ARID1B, SHANK3, ADNP2, ANK2 and CHD8. -
Detailed Characterization of Human Induced Pluripotent Stem Cells Manufactured for Therapeutic Applications
Stem Cell Rev and Rep DOI 10.1007/s12015-016-9662-8 Detailed Characterization of Human Induced Pluripotent Stem Cells Manufactured for Therapeutic Applications Behnam Ahmadian Baghbaderani 1 & Adhikarla Syama2 & Renuka Sivapatham3 & Ying Pei4 & Odity Mukherjee2 & Thomas Fellner1 & Xianmin Zeng3,4 & Mahendra S. Rao5,6 # The Author(s) 2016. This article is published with open access at Springerlink.com Abstract We have recently described manufacturing of hu- help determine which set of tests will be most useful in mon- man induced pluripotent stem cells (iPSC) master cell banks itoring the cells and establishing criteria for discarding a line. (MCB) generated by a clinically compliant process using cord blood as a starting material (Baghbaderani et al. in Stem Cell Keywords Induced pluripotent stem cells . Embryonic stem Reports, 5(4), 647–659, 2015). In this manuscript, we de- cells . Manufacturing . cGMP . Consent . Markers scribe the detailed characterization of the two iPSC clones generated using this process, including whole genome se- quencing (WGS), microarray, and comparative genomic hy- Introduction bridization (aCGH) single nucleotide polymorphism (SNP) analysis. We compare their profiles with a proposed calibra- Induced pluripotent stem cells (iPSCs) are akin to embryonic tion material and with a reporter subclone and lines made by a stem cells (ESC) [2] in their developmental potential, but dif- similar process from different donors. We believe that iPSCs fer from ESC in the starting cell used and the requirement of a are likely to be used to make multiple clinical products. We set of proteins to induce pluripotency [3]. Although function- further believe that the lines used as input material will be used ally identical, iPSCs may differ from ESC in subtle ways, at different sites and, given their immortal status, will be used including in their epigenetic profile, exposure to the environ- for many years or even decades. -
Human Induced Pluripotent Stem Cell–Derived Podocytes Mature Into Vascularized Glomeruli Upon Experimental Transplantation
BASIC RESEARCH www.jasn.org Human Induced Pluripotent Stem Cell–Derived Podocytes Mature into Vascularized Glomeruli upon Experimental Transplantation † Sazia Sharmin,* Atsuhiro Taguchi,* Yusuke Kaku,* Yasuhiro Yoshimura,* Tomoko Ohmori,* ‡ † ‡ Tetsushi Sakuma, Masashi Mukoyama, Takashi Yamamoto, Hidetake Kurihara,§ and | Ryuichi Nishinakamura* *Department of Kidney Development, Institute of Molecular Embryology and Genetics, and †Department of Nephrology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; ‡Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima, Japan; §Division of Anatomy, Juntendo University School of Medicine, Tokyo, Japan; and |Japan Science and Technology Agency, CREST, Kumamoto, Japan ABSTRACT Glomerular podocytes express proteins, such as nephrin, that constitute the slit diaphragm, thereby contributing to the filtration process in the kidney. Glomerular development has been analyzed mainly in mice, whereas analysis of human kidney development has been minimal because of limited access to embryonic kidneys. We previously reported the induction of three-dimensional primordial glomeruli from human induced pluripotent stem (iPS) cells. Here, using transcription activator–like effector nuclease-mediated homologous recombination, we generated human iPS cell lines that express green fluorescent protein (GFP) in the NPHS1 locus, which encodes nephrin, and we show that GFP expression facilitated accurate visualization of nephrin-positive podocyte formation in -
Examination of the Expression and Prognostic Significance of Dlgaps in Gastric Cancer Using the TCGA Database and Bioinformatic Analysis
MOLECULAR MEDICINE REPORTS 18: 5621-5629, 2018 Examination of the expression and prognostic significance of DLGAPs in gastric cancer using the TCGA database and bioinformatic analysis JIAXIN LIU1, ZHAO LIU2, XIAOZHI ZHANG3, TUOTUO GONG3 and DEMAO YAO1 Departments of 1Gerontological Surgery, 2Oncological Surgery and 3Radiation Oncology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China Received February 3, 2018; Accepted September 21, 2018 DOI: 10.3892/mmr.2018.9574 Abstract. The discs large-associated protein (DLGAP) Introduction family has been implicated in psychological and neurological diseases. However, few studies have explored the association Gastric cancer (GC) is a highly aggressive disease, with an inci- between the expression of DLGAPs and different types of dence that is ranked fifth among all types of cancers worldwide cancer. Therefore, the present study analyzed the status of in recent years (1,2). There are nearly 1,000,000 new cases of DLGAPs in gastric cancer (GC) using bioinformatic tools. GC diagnosed globally each year (3). The majority of patients Analyses of data obtained from The Cancer Genome Atlas and succumb to GC due to late recurrence or distant metastasis, and Gene Expression Omnibus databases revealed that there was the 5-year survival rate for GC patients is <5% (4). Thus, there selective upregulation of DLGAP4 and DLGAP5 expression is an urgent requirement to identify biomarkers associated with in GC tissues when compared with normal gastric tissues. the prognosis of patients with GC. Although some targets are In addition, survival analysis using OncoLnc indicated that currently in clinical use, including human epidermal growth high expression of DLGAP4 was significantly correlated factor receptor 2 (5,6), vascular endothelial growth factor with shorter overall survival for all GC patients. -
Small Non-Coding-RNA in Gynecological Malignancies
cancers Review Small Non-Coding-RNA in Gynecological Malignancies Shailendra Kumar Dhar Dwivedi 1 , Geeta Rao 2, Anindya Dey 1, Priyabrata Mukherjee 2,3, Jonathan D. Wren 4,5,6 and Resham Bhattacharya 1,3,7,* 1 Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; [email protected] (S.K.D.D.); [email protected] (A.D.) 2 Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; [email protected] (G.R.); [email protected] (P.M.) 3 Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA 4 Biochemistry and Molecular Biology Department, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; [email protected] 5 Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA 6 Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA 7 Department of Cell Biology, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA * Correspondence: [email protected] Simple Summary: Gynecologic malignancies are among the leading cause of female mortality worldwide, and their management is complicated by late diagnosis and acquired therapy resistance. Although altered DNA code, leading to aberrant protein expression, is indispensable for cancer Citation: Dwivedi, S.K.D.; Rao, G.; initiation and progression, from the current literature it is clear that, not only proteins, but also Dey, A.; Mukherjee, P.; Wren, J.D.; noncoding RNA, which does not translate into proteins, can also be instrumental. -
Expression of Periaxin (PRX) Specifically in the Human
www.nature.com/scientificreports OPEN Expression of periaxin (PRX) specifcally in the human cerebrovascular system: PDZ Received: 6 November 2017 Accepted: 13 June 2018 domain-mediated strengthening Published: xx xx xxxx of endothelial barrier function Michael M. Wang1,2,3,4, Xiaojie Zhang1,2, Soo Jung Lee1,2, Snehaa Maripudi1,3, Richard F. Keep2,4,5, Allison M. Johnson4,6,7, Svetlana M. Stamatovic6,7 & Anuska V. Andjelkovic4,6,7 Regulation of cerebral endothelial cell function plays an essential role in changes in blood-brain barrier permeability. Proteins that are important for establishment of endothelial tight junctions have emerged as critical molecules, and PDZ domain containing-molecules are among the most important. We have discovered that the PDZ-domain containing protein periaxin (PRX) is expressed in human cerebral endothelial cells. Surprisingly, PRX protein is not detected in brain endothelium in other mammalian species, suggesting that it could confer human-specifc vascular properties. In endothelial cells, PRX is predominantly localized to the nucleus and not tight junctions. Transcriptome analysis shows that PRX expression suppresses, by at least 50%, a panel of infammatory markers, of which 70% are Type I interferon response genes; only four genes were signifcantly activated by PRX expression. When expressed in mouse endothelial cells, PRX strengthens barrier function, signifcantly increases transendothelial electrical resistance (~35%; p < 0.05), and reduces the permeability of a wide range of molecules. The PDZ domain of PRX is necessary and sufcient for its barrier enhancing properties, since a splice variant (S-PRX) that contains only the PDZ domain, also increases barrier function. PRX also attenuates the permeability enhancing efects of lipopolysaccharide. -
The DLGAP Family: Neuronal Expression, Function and Role in Brain Disorders Andreas H
Rasmussen et al. Molecular Brain (2017) 10:43 DOI 10.1186/s13041-017-0324-9 REVIEW Open Access The DLGAP family: neuronal expression, function and role in brain disorders Andreas H. Rasmussen1, Hanne B. Rasmussen2 and Asli Silahtaroglu1* Abstract The neurotransmitter glutamate facilitates neuronal signalling at excitatory synapses. Glutamate is released from the presynaptic membrane into the synaptic cleft. Across the synaptic cleft glutamate binds to both ion channels and metabotropic glutamate receptors at the postsynapse, which expedite downstream signalling in the neuron. The postsynaptic density, a highly specialized matrix, which is attached to the postsynaptic membrane, controls this downstream signalling. The postsynaptic density also resets the synapse after each synaptic firing. It is composed of numerous proteins including a family of Discs large associated protein 1, 2, 3 and 4 (DLGAP1-4) that act as scaffold proteins in the postsynaptic density. They link the glutamate receptors in the postsynaptic membrane to other glutamate receptors, to signalling proteins and to components of the cytoskeleton. With the central localisation in the postsynapse, the DLGAP family seems to play a vital role in synaptic scaling by regulating the turnover of both ionotropic and metabotropic glutamate receptors in response to synaptic activity. DLGAP family has been directly linked to a variety of psychological and neurological disorders. In this review we focus on the direct and indirect role of DLGAP family on schizophrenia as well as other brain diseases. Keywords: DLGAP1, DLGAP2, DLGAP3, DLGAP4, SAPAP, PSD, GKAP, Schizophrenia, Scaffold proteins, Synaptic scaling Introduction interaction partners, DLGAP1–4 proteins are likely to play The postsynaptic density (PSD) is a highly specialized a role in multiple processes of the PSD. -
A SARS-Cov-2 Protein Interaction Map Reveals Targets for Drug Repurposing
Article A SARS-CoV-2 protein interaction map reveals targets for drug repurposing https://doi.org/10.1038/s41586-020-2286-9 A list of authors and affiliations appears at the end of the paper Received: 23 March 2020 Accepted: 22 April 2020 A newly described coronavirus named severe acute respiratory syndrome Published online: 30 April 2020 coronavirus 2 (SARS-CoV-2), which is the causative agent of coronavirus disease 2019 (COVID-19), has infected over 2.3 million people, led to the death of more than Check for updates 160,000 individuals and caused worldwide social and economic disruption1,2. There are no antiviral drugs with proven clinical efcacy for the treatment of COVID-19, nor are there any vaccines that prevent infection with SARS-CoV-2, and eforts to develop drugs and vaccines are hampered by the limited knowledge of the molecular details of how SARS-CoV-2 infects cells. Here we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identifed the human proteins that physically associated with each of the SARS-CoV-2 proteins using afnity-purifcation mass spectrometry, identifying 332 high-confdence protein–protein interactions between SARS-CoV-2 and human proteins. Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (of which, 29 drugs are approved by the US Food and Drug Administration, 12 are in clinical trials and 28 are preclinical compounds). We screened a subset of these in multiple viral assays and found two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the sigma-1 and sigma-2 receptors.