Association and Haplotype Analyses of Positional Candidate Genes In

Total Page:16

File Type:pdf, Size:1020Kb

Association and Haplotype Analyses of Positional Candidate Genes In University of Nebraska - Lincoln DigitalCommons@University of Nebraska - Lincoln Faculty Papers and Publications in Animal Science Animal Science Department 2009 Association and Haplotype Analyses of Positional Candidate Genes in Five Genomic Regions Linked to Scrotal Hernia in Commercial Pig Lines Zhi-Qiang Du Iowa State University Xia Zhao Iowa State University Natascha Vukasinovic Newsham Choice Genetics Fernanda Rodriguez Monsanto Archie C. Clutter Newsham Choice Genetics See next page for additional authors Follow this and additional works at: https://digitalcommons.unl.edu/animalscifacpub Part of the Genetics and Genomics Commons, and the Meat Science Commons Du, Zhi-Qiang; Zhao, Xia; Vukasinovic, Natascha; Rodriguez, Fernanda; Clutter, Archie C.; and Rothschild, Max F., "Association and Haplotype Analyses of Positional Candidate Genes in Five Genomic Regions Linked to Scrotal Hernia in Commercial Pig Lines" (2009). Faculty Papers and Publications in Animal Science. 1033. https://digitalcommons.unl.edu/animalscifacpub/1033 This Article is brought to you for free and open access by the Animal Science Department at DigitalCommons@University of Nebraska - Lincoln. It has been accepted for inclusion in Faculty Papers and Publications in Animal Science by an authorized administrator of DigitalCommons@University of Nebraska - Lincoln. Authors Zhi-Qiang Du, Xia Zhao, Natascha Vukasinovic, Fernanda Rodriguez, Archie C. Clutter, and Max F. Rothschild This article is available at DigitalCommons@University of Nebraska - Lincoln: https://digitalcommons.unl.edu/animalscifacpub/ 1033 Association and Haplotype Analyses of Positional Candidate Genes in Five Genomic Regions Linked to Scrotal Hernia in Commercial Pig Lines Zhi-Qiang Du1, Xia Zhao1, Natascha Vukasinovic2, Fernanda Rodriguez3, Archie C. Clutter2, Max F. Rothschild1* 1 Department of Animal Science and Center for Integrated Animal Genomics, Iowa State University, Ames, Iowa, United States of America, 2 Newsham Choice Genetics, West Des Moines, Iowa, United States of America, 3 Monsanto Company, Saint Louis, Missouri, United States of America Abstract Scrotal hernia in pigs is a complex trait likely affected by genetic and environmental factors. A large-scale association analysis of positional and functional candidate genes was conducted in four previously identified genomic regions linked to hernia susceptibility on Sus scrofa chromosomes 2 and 12, as well as the fifth region around 67 cM on chromosome 2, respectively. In total, 151 out of 416 SNPs discovered were genotyped successfully. Using a family-based analysis we found that four regions surrounding ELF5, KIF18A, COL23A1 on chromosome 2, and NPTX1 on chromosome 12, respectively, may contain the genetic variants important for the development of the scrotal hernia in pigs. These findings were replicated in another case-control dataset. The SNPs around the ELF5 region were in high linkage disequilibrium with each other, and a haplotype containing SNPs from ELF5 and CAT was highly significantly associated with hernia development. Extensive re- sequencing work focused on the KIF18A gene did not detect any further SNPs with extensive association signals. These genes may be involved in the estrogen receptor signaling pathway (KIF18A and NPTX1), the epithelial-mesenchymal transition (ELF5) and the collagen metabolism pathway (COL23A1), which are associated with the important molecular characteristics of hernia pathophysiology. Further investigation on the molecular mechanisms of these genes may provide more molecular clues on hernia development in pigs. Citation: Du Z-Q, Zhao X, Vukasinovic N, Rodriguez F, Clutter AC, et al. (2009) Association and Haplotype Analyses of Positional Candidate Genes in Five Genomic Regions Linked to Scrotal Hernia in Commercial Pig Lines. PLoS ONE 4(3): e4837. doi:10.1371/journal.pone.0004837 Editor: Ellen A. A. Nollen, University Medical Center Groningen, Netherlands Received October 31, 2008; Accepted February 6, 2009; Published March 16, 2009 Copyright: ß 2009 Du et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: We appreciate the financial support by Monsanto Choice Genetics and Newsham Choice Genetics, and the additional financial support provided by State of Iowa and Hatch Funds and the support from the College of Agriculture and Life Science in Iowa State University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected] Introduction Our previous genome-wide linkage studies have identified several genomic regions related to the hernia incidence in Most of the inguinal and scrotal hernias (hernia inguinalis and Pietrain-based lines [18,19]. The quantitative trait loci (QTL) scrotalis) are birth defects in human, under the control of genetic regions on Sus scrofa chromosomes (SSC) 2 and 12 have been and environmental factors. However, the molecular mechanism of replicated in seven other independent paternal families derived etiology remains elusive [1–5]. In the pig breeding industry, from three commercial Pietrain-based pig lines [19]. Moreover, in infrequent incidence of inguinal and scrotal hernias can happen the same genomic regions on SSC2 and SSC12, QTL have been for certain pig breeds and lines and genetic factors are believed to drive the hernia development [6–8]. Without clinical examination, identified in another pig breed, Landrace, using affected sib pairs, these two defects cannot be easily distinguished, and most of the which suggests that common genetic origins may be involved even time, this is the case. for different pig populations [20]. We continued to refine the Genome-wide association analyses (GWA) have now been interesting regions by LD analysis, and found three independent frequently applied in the search for human disease susceptibility regions, at approximately 3, 42 and 65 cM on SSC2, and the first loci [9]. This approach could not be realized without the 20 cM region on SSC12, with genes segregating for the risk to advancement of next-generation sequencing and genotyping develop inguinal and scrotal hernias [19]. technologies, as well as the massive efforts spent in the annotation Since the pig whole genome sequencing project is not yet of the structural and functional properties of the human genome completed, we had to use all available sequence information in (HapMap and ENCODE projects) [10,11]. Moreover, attempts to pigs, as well as the comparative information from the human identify the causal genes or gene subnetworks for a disease-linked genome. Taking into consideration the practical concerns of genomic region have employed large-scale candidate gene experimental power in the design of GWA and candidate gene association analyses [12–15], linkage disequilibrium (LD) fine association analyses in human disease studies [9,21,22], and the mapping [16], and more recently, reversely engineered molecular genomic distribution of LD status in pigs [23], we selected 99 posi- network methods [17]. tional candidate genes located in the aforementioned interesting PLoS ONE | www.plosone.org 1 March 2009 | Volume 4 | Issue 3 | e4837 Positional Genes & Pig Hernia regions on SSC2 and SSC12 to conduct a regional large-scale three genes located in or close to region II, the E74-like factor 5 resequencing and association study for the genetic causes of (ELF5), HIPK3 and the kinesin family member 18A (KIF18A), scrotal/inguinal hernia. The possible dysfunction of these genes were highly significantly associated with scrotal hernia (p,0.01) can result in the aberrant collagen metabolism (the most probable (Table 1, Table S2). Even after FDR correction, they were still reason considered for hernia development) [24–27], the smooth significant at p,0.05. The localization of the four SNPs were muscle breakdown [28,29], an altered apoptosis pathway [30], right under the hernia QTL region around 42 cM on SSC2 the sex hormone deregulation [31–33], and the dedifferentiation (Figure 1A), and they were in high LD with each other of fibroblasts derived from the stem cells during epithelial- (Figure 1D). Furthermore, a common haplotype formed by five mesenchymal transition (EMT) [34]. SNPs, ELF5-1, ELF5-3, ELF5-5, ELF5-8 and EHF1, from ELF5 and a neighboring gene EHF, but not HIPK3 and KIF18A, was Results significantly associated with scrotal hernia (p,0.001). In order to further dissect the association from region II on Based on the nucleotide sequence information provided by the SSC2, we added 26 markers surrounding the interesting genes, markers in the three regions associated with scrotal hernia on ELF5 (1 MB region) and KIF18A (6 MB region) (Figure 1E, Table SSC2 at approximately 3, 42 and 65 cM, which existed in S1). At this stage of the genotyping and analyses, the SNP in intron genomic DNA sequences (NCBI accession numbers: BH021488, 3ofKIF18A gave the highest association signal. Furthermore, we DQ648562 and CL352219), we blasted them against the NCBI sequenced 15 exons (exons 2–16), except exon 1 of KIF18A, which nucleotide database, and selected a first set of four important were found in an unordered sequenced BAC clone CH242-13K2 candidate genes distributed in the three specific sub-regions, i.e.
Recommended publications
  • CD29 Identifies IFN-Γ–Producing Human CD8+ T Cells With
    + 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.
    [Show full text]
  • Novel Proteins Regulated by Mtor in Subependymal Giant Cell Astrocytomas of Patients with Tuberous Sclerosis Complex and New Therapeutic Implications
    The American Journal of Pathology, Vol. 176, No. 4, April 2010 Copyright © American Society for Investigative Pathology DOI: 10.2353/ajpath.2010.090950 Molecular Pathogenesis of Genetic and Inherited Diseases Novel Proteins Regulated by mTOR in Subependymal Giant Cell Astrocytomas of Patients with Tuberous Sclerosis Complex and New Therapeutic Implications Magdalena Ewa Tyburczy,* Katarzyna Kotulska,† and demonstrated an effective modulation of SEGA Piotr Pokarowski,‡ Jakub Mieczkowski,* growth by pharmacological inhibition of both Joanna Kucharska,* Wieslawa Grajkowska,† mTOR and extracellular signal-regulated kinase sig- Maciej Roszkowski,§ Sergiusz Jozwiak,† naling pathways, which could represent a novel ther- and Bozena Kaminska* apeutic approach. (Am J Pathol 2010, 176:1878–1890; DOI: 10.2353/ajpath.2010.090950) From the Laboratory of Transcription Regulation,* the Nencki Institute of Experimental Biology, Warsaw; the Departments of Neurology and Epileptology,† and Neurosurgery,§ the Children’s Subependymal giant cell astrocytomas (SEGAs) are rare, Memorial Health Institute, Warsaw; and the Faculty of low-grade brain tumors (World Health Organization Grade I) Mathematics, Informatics, and Mechanics,‡ University of of a mixed glioneuronal lineage.1,2 They are observed in Warsaw, Poland 10% to 20% of patients with tuberous sclerosis complex (TSC) and are the major cause of morbidity in children and young adults with TSC.3 The disease affects about one in Subependymal giant cell astrocytomas (SEGAs) are 6000 people, is characterized by the formation of benign rare brain tumors associated with tuberous sclerosis tumors in multiple organs (mainly brain, heart, kidneys, skin, complex (TSC), a disease caused by mutations in TSC1 or lungs), and is often associated with epilepsy, mental or TSC2, resulting in enhancement of mammalian retardation, and autism.4,5 Tuberous sclerosis complex is target of rapamycin (mTOR) activity, dysregulation of caused by mutation in one of two tumor suppressor genes, cell growth, and tumorigenesis.
    [Show full text]
  • 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.
    [Show full text]
  • Gene Expression Changes in a Tumor Xenograft by a Pyrrole-Imidazole Polyamide
    Gene expression changes in a tumor xenograft by a pyrrole-imidazole polyamide Jevgenij A. Raskatova, Nicholas G. Nickolsa,b, Amanda E. Hargrovea, Georgi K. Marinovc, Barbara Woldc, and Peter B. Dervana,1 aDivision of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125; bDepartment of Radiation Oncology, David Geffen School of Medicine of the University of California Los Angeles, Los Angeles, CA 90095-6951; and cDivision of Biology, California Institute of Technology, Pasadena, CA 91125 Contributed by Peter B. Dervan, August 20, 2012 (sent for review July 10, 2012) Gene regulation by DNA binding small molecules could have impor- efforts established that the polyamide 2 was capable of modulat- tant therapeutic applications. This study reports the investigation ing a subset of TNF-inducible genes (10). Among the strongly of a DNA-binding pyrrole-imidazole polyamide targeted to bind affected genes we had identified CCL2 and SERPINE1 as highly the DNA sequence 5′-WGGWWW-3′ with reference to its potency repressed targets of 2. in a subcutaneous xenograft tumor model. The molecule is capable The basal expression levels of CCL2 and SERPINE1 were suf- of trafficking to the tumor site following subcutaneous injection ficiently high to enable the study of polyamide effects in the un- and modulates transcription of select genes in vivo. An FITC-la- induced state. We found that both 1 and 2 reduced the levels of beled analogue of this polyamide can be detected in tumor-derived the two transcripts, but the effects exerted by 1 were substantially cells by confocal microscopy. RNA deep sequencing (RNA-seq) of more pronounced (Fig.
    [Show full text]
  • Indications of Linkage and Association of Gilles De La Tourette Syndrome in Two Independent Family Samples: 17Q25 Is a Putative Susceptibility Region P
    Am. J. Hum. Genet. 75:545–560, 2004 Indications of Linkage and Association of Gilles de la Tourette Syndrome in Two Independent Family Samples: 17q25 Is a Putative Susceptibility Region P. Paschou,1 Y. Feng,2 A. J. Pakstis,1 W. C. Speed,1 M. M. DeMille,1 J. R. Kidd,1 B. Jaghori,2 R. Kurlan,5 D. L. Pauls,6 P. Sandor,2,3 C. L. Barr,2,4 and K. K. Kidd1 1Department of Genetics, Yale University School of Medicine, New Haven; 2Toronto Western Research Institute, University Health Network, 3Department of Psychiatry, University of Toronto, and 4Department of Psychiatry, Brain and Behaviour Programme, The Hospital for Sick Children, Toronto; 5Cognitive and Behavioral Neurology Unit, Department of Neurology, University of Rochester School of Medicine, Rochester, NY; and 6Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA Gilles de la Tourette syndrome (GTS) is characterized by multiple motor and phonic tics and high comorbidity rates with other neurobehavioral disorders. It is hypothesized that frontal-subcortical pathways and a complex genetic background are involved in the etiopathogenesis of the disorder. The genetic basis of GTS remains elusive. However, several genomic regions have been implicated. Among them, 17q25 appears to be of special interest, as suggested by various independent investigators. In the present study, we explored the possibility that 17q25 con- tributes to the genetic component of GTS. The initial scan of chromosome 17 performed on two large pedigrees provided a nonparametric LOD score of 2.41 near D17S928. Fine mapping with 17 additional microsatellite markers increased the peak to 2.61 (P p .002 ).
    [Show full text]
  • 393LN V 393P 344SQ V 393P Probe Set Entrez Gene
    393LN v 393P 344SQ v 393P Entrez fold fold probe set Gene Gene Symbol Gene cluster Gene Title p-value change p-value change chemokine (C-C motif) ligand 21b /// chemokine (C-C motif) ligand 21a /// chemokine (C-C motif) ligand 21c 1419426_s_at 18829 /// Ccl21b /// Ccl2 1 - up 393 LN only (leucine) 0.0047 9.199837 0.45212 6.847887 nuclear factor of activated T-cells, cytoplasmic, calcineurin- 1447085_s_at 18018 Nfatc1 1 - up 393 LN only dependent 1 0.009048 12.065 0.13718 4.81 RIKEN cDNA 1453647_at 78668 9530059J11Rik1 - up 393 LN only 9530059J11 gene 0.002208 5.482897 0.27642 3.45171 transient receptor potential cation channel, subfamily 1457164_at 277328 Trpa1 1 - up 393 LN only A, member 1 0.000111 9.180344 0.01771 3.048114 regulating synaptic membrane 1422809_at 116838 Rims2 1 - up 393 LN only exocytosis 2 0.001891 8.560424 0.13159 2.980501 glial cell line derived neurotrophic factor family receptor alpha 1433716_x_at 14586 Gfra2 1 - up 393 LN only 2 0.006868 30.88736 0.01066 2.811211 1446936_at --- --- 1 - up 393 LN only --- 0.007695 6.373955 0.11733 2.480287 zinc finger protein 1438742_at 320683 Zfp629 1 - up 393 LN only 629 0.002644 5.231855 0.38124 2.377016 phospholipase A2, 1426019_at 18786 Plaa 1 - up 393 LN only activating protein 0.008657 6.2364 0.12336 2.262117 1445314_at 14009 Etv1 1 - up 393 LN only ets variant gene 1 0.007224 3.643646 0.36434 2.01989 ciliary rootlet coiled- 1427338_at 230872 Crocc 1 - up 393 LN only coil, rootletin 0.002482 7.783242 0.49977 1.794171 expressed sequence 1436585_at 99463 BB182297 1 - up 393
    [Show full text]
  • Peripheral Nerve Single-Cell Analysis Identifies Mesenchymal Ligands That Promote Axonal Growth
    Research Article: New Research Development Peripheral Nerve Single-Cell Analysis Identifies Mesenchymal Ligands that Promote Axonal Growth Jeremy S. Toma,1 Konstantina Karamboulas,1,ª Matthew J. Carr,1,2,ª Adelaida Kolaj,1,3 Scott A. Yuzwa,1 Neemat Mahmud,1,3 Mekayla A. Storer,1 David R. Kaplan,1,2,4 and Freda D. Miller1,2,3,4 https://doi.org/10.1523/ENEURO.0066-20.2020 1Program in Neurosciences and Mental Health, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada, 2Institute of Medical Sciences University of Toronto, Toronto, Ontario M5G 1A8, Canada, 3Department of Physiology, University of Toronto, Toronto, Ontario M5G 1A8, Canada, and 4Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1A8, Canada Abstract Peripheral nerves provide a supportive growth environment for developing and regenerating axons and are es- sential for maintenance and repair of many non-neural tissues. This capacity has largely been ascribed to paracrine factors secreted by nerve-resident Schwann cells. Here, we used single-cell transcriptional profiling to identify ligands made by different injured rodent nerve cell types and have combined this with cell-surface mass spectrometry to computationally model potential paracrine interactions with peripheral neurons. These analyses show that peripheral nerves make many ligands predicted to act on peripheral and CNS neurons, in- cluding known and previously uncharacterized ligands. While Schwann cells are an important ligand source within injured nerves, more than half of the predicted ligands are made by nerve-resident mesenchymal cells, including the endoneurial cells most closely associated with peripheral axons. At least three of these mesen- chymal ligands, ANGPT1, CCL11, and VEGFC, promote growth when locally applied on sympathetic axons.
    [Show full text]
  • Targets of the Tumor Suppressor Mir-200 in Regulation of the Epithelial–Mesenchymal Transition in Cancer
    Published OnlineFirst October 10, 2011; DOI: 10.1158/0008-5472.CAN-11-0964 Cancer Tumor and Stem Cell Biology Research Targets of the Tumor Suppressor miR-200 in Regulation of the Epithelial–Mesenchymal Transition in Cancer Mark J. Schliekelman1 , Don L. Gibbons2,3, Vitor M. Faca1, Chad J. Creighton4, Zain H. Rizvi2, Qing Zhang1, Chee-Hong Wong1, Hong Wang1, Christin Ungewiss2, Young-Ho Ahn2, Dong-Hoon Shin2, Jonathan M. Kurie2, and Samir M. Hanash1 Abstract The microRNA-200 (miR-200) family restricts epithelial–mesenchymal transition (EMT) and metastasis in tumor cell lines derived from mice that develop metastatic lung adenocarcinoma. To determine the mechanisms responsible for EMT and metastasis regulated by this microRNA, we conducted a global liquid chromatography/ tandem mass spectrometry analysis to compare metastatic and nonmetastatic murine lung adenocarcinoma cells which had undergone EMT because of loss of miR-200. An analysis of syngeneic tumors generated by these cells identified multiple novel proteins linked to metastasis. In particular, the analysis of conditioned media, cell surface proteins, and whole-cell lysates from metastatic and nonmetastatic cells revealed large-scale modifica- tions in the tumor microenvironment. Specific increases were documented in extracellular matrix (ECM) proteins, peptidases, and changes in distribution of cell adhesion proteins in the metastatic cell lines. Integrating proteomic data from three subproteomes, we defined constituents of a multilayer protein network that both regulated and mediated the effects of TGFb. Lastly, we identified ECM proteins and peptidases that were directly regulated by miR-200. Taken together, our results reveal how expression of miR-200 alters the tumor microenvironment to inhibit the processes of EMT and metastasis.
    [Show full text]
  • Detection of H3k4me3 Identifies Neurohiv Signatures, Genomic
    viruses Article Detection of H3K4me3 Identifies NeuroHIV Signatures, Genomic Effects of Methamphetamine and Addiction Pathways in Postmortem HIV+ Brain Specimens that Are Not Amenable to Transcriptome Analysis Liana Basova 1, Alexander Lindsey 1, Anne Marie McGovern 1, Ronald J. Ellis 2 and Maria Cecilia Garibaldi Marcondes 1,* 1 San Diego Biomedical Research Institute, San Diego, CA 92121, USA; [email protected] (L.B.); [email protected] (A.L.); [email protected] (A.M.M.) 2 Departments of Neurosciences and Psychiatry, University of California San Diego, San Diego, CA 92103, USA; [email protected] * Correspondence: [email protected] Abstract: Human postmortem specimens are extremely valuable resources for investigating trans- lational hypotheses. Tissue repositories collect clinically assessed specimens from people with and without HIV, including age, viral load, treatments, substance use patterns and cognitive functions. One challenge is the limited number of specimens suitable for transcriptional studies, mainly due to poor RNA quality resulting from long postmortem intervals. We hypothesized that epigenomic Citation: Basova, L.; Lindsey, A.; signatures would be more stable than RNA for assessing global changes associated with outcomes McGovern, A.M.; Ellis, R.J.; of interest. We found that H3K27Ac or RNA Polymerase (Pol) were not consistently detected by Marcondes, M.C.G. Detection of H3K4me3 Identifies NeuroHIV Chromatin Immunoprecipitation (ChIP), while the enhancer H3K4me3 histone modification was Signatures, Genomic Effects of abundant and stable up to the 72 h postmortem. We tested our ability to use H3K4me3 in human Methamphetamine and Addiction prefrontal cortex from HIV+ individuals meeting criteria for methamphetamine use disorder or not Pathways in Postmortem HIV+ Brain (Meth +/−) which exhibited poor RNA quality and were not suitable for transcriptional profiling.
    [Show full text]
  • Table S1. 103 Ferroptosis-Related Genes Retrieved from the Genecards
    Table S1. 103 ferroptosis-related genes retrieved from the GeneCards. Gene Symbol Description Category GPX4 Glutathione Peroxidase 4 Protein Coding AIFM2 Apoptosis Inducing Factor Mitochondria Associated 2 Protein Coding TP53 Tumor Protein P53 Protein Coding ACSL4 Acyl-CoA Synthetase Long Chain Family Member 4 Protein Coding SLC7A11 Solute Carrier Family 7 Member 11 Protein Coding VDAC2 Voltage Dependent Anion Channel 2 Protein Coding VDAC3 Voltage Dependent Anion Channel 3 Protein Coding ATG5 Autophagy Related 5 Protein Coding ATG7 Autophagy Related 7 Protein Coding NCOA4 Nuclear Receptor Coactivator 4 Protein Coding HMOX1 Heme Oxygenase 1 Protein Coding SLC3A2 Solute Carrier Family 3 Member 2 Protein Coding ALOX15 Arachidonate 15-Lipoxygenase Protein Coding BECN1 Beclin 1 Protein Coding PRKAA1 Protein Kinase AMP-Activated Catalytic Subunit Alpha 1 Protein Coding SAT1 Spermidine/Spermine N1-Acetyltransferase 1 Protein Coding NF2 Neurofibromin 2 Protein Coding YAP1 Yes1 Associated Transcriptional Regulator Protein Coding FTH1 Ferritin Heavy Chain 1 Protein Coding TF Transferrin Protein Coding TFRC Transferrin Receptor Protein Coding FTL Ferritin Light Chain Protein Coding CYBB Cytochrome B-245 Beta Chain Protein Coding GSS Glutathione Synthetase Protein Coding CP Ceruloplasmin Protein Coding PRNP Prion Protein Protein Coding SLC11A2 Solute Carrier Family 11 Member 2 Protein Coding SLC40A1 Solute Carrier Family 40 Member 1 Protein Coding STEAP3 STEAP3 Metalloreductase Protein Coding ACSL1 Acyl-CoA Synthetase Long Chain Family Member 1 Protein
    [Show full text]
  • Gene Expression Changes in a Tumor Xenograft by a Pyrrole-Imidazole
    Supporting Information Raskatov et al. 10.1073/pnas.1214267109 SI Text protein is a receptor for members of the epidermal growth factor RNA-Sequencing (RNA-Seq) Processing Needs to Take the Presence of family. EGFR is a cell surface protein that binds to epidermal Two Transcriptomes into Account. Initial attempts to map and quan- growth factor. Binding of the protein to a ligand induces receptor tify RNA-seq data using the commonly used software packages dimerization and tyrosine autophosphorylation and leads to cell TopHat and Cufflinks (1) using just the human genome as a proliferation. Mutations in this gene are associated with lung can- reference resulted in unsatisfactory results (which was demon- cer. Multiple alternatively spliced transcript variants that encode strated by control quantitative reverse transcription-PCR (qRT- different protein isoforms have been found for this gene. (pro- PCR) experiments) likely due to the presence of significant vided by refSeq, July 2010). amounts of host RNA in the libraries and the extensive sequence homology between highly conserved mouse and human genes. MMP28: Official symbol: MMP28 and name: Matrix metallopeptidase We investigated this by comparing the mapping efficiencies of the 28. Proteins of the matrix metalloproteinase family are involved in tumor samples to the human genome (hg19) to the mouse (mm9). the breakdown of extracellular matrix for both normal physiolo- The ratio between the mapping percentages to hg19 and mm9 is gical processes, such as embryonic development, reproduction reflective of the tumor composition and was found to lay typically and tissue remodeling, and disease processes, such as asthma and between 1.3 and 1.4, suggesting some 40% of the tumor mRNA to metastasis.
    [Show full text]
  • Derived Xenografts Highlights the Role of REST in Neuroendocrine Differentiation of Castration- Resistant Prostate Cancer Amilcar Flores-Morales1,2,3, Tobias B
    Published OnlineFirst October 1, 2018; DOI: 10.1158/1078-0432.CCR-18-0729 Biology of Human Tumors Clinical Cancer Research Proteogenomic Characterization of Patient- Derived Xenografts Highlights the Role of REST in Neuroendocrine Differentiation of Castration- Resistant Prostate Cancer Amilcar Flores-Morales1,2,3, Tobias B. Bergmann1,2, Charlotte Lavallee1,2, Tanveer S. Batth3, Dong Lin4, Mads Lerdrup5, Stine Friis1,2, Anette Bartels1,2, Gitte Kristensen6, Agnieszka Krzyzanowska7, Hui Xue4, Ladan Fazli4, Klaus H. Hansen5, Martin A. Røder6, Klaus Brasso6, Jose M. Moreira1,2, Anders Bjartell7, Yuzhuo Wang4, Jesper V. Olsen3, Colin C. Collins4, and Diego Iglesias-Gato1,2 Abstract Background: An increasing number of castration-resistant and elevated in NEPC, while the reduced levels of proteins prostate cancer (CRPC) tumors exhibit neuroendocrine (NE) involved in mitochondrial functions suggested a prevalent features. NE prostate cancer (NEPC) has poor prognosis, and glycolytic metabolism of NEPC tumors. Integration of the its development is poorly understood. REST chromatin bound regions with expression changes Experimental Design: We applied mass spectrometry– indicated a direct role of REST in regulating neuronal gene based proteomics to a unique set of 17 prostate cancer expression in prostate cancer cells. Mechanistically, deple- patient–derived xenografts (PDX) to characterize the effects tion of REST led to cell-cycle arrest in G1, which could be of castration in vivo, and the proteome differences between rescued by p53 knockdown. Finally, the expression of the NEPC and prostate adenocarcinomas. Genome-wide profiling REST-regulated gene secretagogin (SCGN) correlated with of REST-occupied regions in prostate cancer cells was corre- an increased risk of suffering disease relapse after radical lated to the expression changes in vivo to investigate the role of prostatectomy.
    [Show full text]