Selection Signatures in Two Oldest Russian Native Cattle Breeds Revealed Using High- Density Single Nucleotide Polymorphism Analysis

Total Page:16

File Type:pdf, Size:1020Kb

Selection Signatures in Two Oldest Russian Native Cattle Breeds Revealed Using High- Density Single Nucleotide Polymorphism Analysis PLOS ONE RESEARCH ARTICLE Selection signatures in two oldest Russian native cattle breeds revealed using high- density single nucleotide polymorphism analysis Natalia Anatolievna Zinovieva1*, Arsen Vladimirovich Dotsev1, Alexander Alexandrovich Sermyagin1, Tatiana Evgenievna Deniskova1, Alexandra 1 1 2 Sergeevna Abdelmanova , Veronika Ruslanovna KharzinovaID , Johann SoÈ lkner , a1111111111 Henry Reyer3, Klaus Wimmers3, Gottfried Brem1,4 a1111111111 a1111111111 1 L.K. Ernst Federal Science Center for Animal Husbandry, Federal Agency of Scientific Organizations, settl. Dubrovitzy, Podolsk Region, Moscow Province, Russia, 2 Division of Livestock Sciences, University of a1111111111 Natural Resources and Life Sciences, Vienna, Austria, 3 Institute of Genome Biology, Leibniz Institute for a1111111111 Farm Animal Biology [FBN], Dummerstorf, Germany, 4 Institute of Animal Breeding and Genetics, University of Veterinary Medicine [VMU], Vienna, Austria * [email protected] OPEN ACCESS Citation: Zinovieva NA, Dotsev AV, Sermyagin AA, Abstract Deniskova TE, Abdelmanova AS, Kharzinova VR, et al. (2020) Selection signatures in two oldest Native cattle breeds can carry specific signatures of selection reflecting their adaptation to Russian native cattle breeds revealed using high- the local environmental conditions and response to the breeding strategy used. In this density single nucleotide polymorphism analysis. study, we comprehensively analysed high-density single nucleotide polymorphism (SNP) PLoS ONE 15(11): e0242200. https://doi.org/ genotypes to characterise the population structure and detect the selection signatures in 10.1371/journal.pone.0242200 Russian native Yaroslavl and Kholmogor dairy cattle breeds, which have been little influ- Editor: Gyaneshwer Chaubey, Banaras Hindu enced by introgression with transboundary breeds. Fifty-six samples of pedigree-recorded University, INDIA purebred animals, originating from different breeding farms and representing different sire Received: May 29, 2020 lines, of the two studied breeds were genotyped using a genome-wide bovine genotyping Accepted: October 29, 2020 array (Bovine HD BeadChip). Three statistical analysesÐcalculation of fixation index (FST) Published: November 16, 2020 for each SNP for the comparison of the pairs of breeds, hapFLK analysis, and estimation of Peer Review History: PLOS recognizes the the runs of homozygosity (ROH) islands shared in more than 50% of animalsÐwere com- benefits of transparency in the peer review bined for detecting the selection signatures in the genome of the studied cattle breeds. We process; therefore, we enable the publication of confirmed nine and six known regions under putative selection in the genomes of Yaroslavl all of the content of peer review and author and Kholmogor cattle, respectively; the flanking positions of most of these regions were elu- responses alongside final, published articles. The editorial history of this article is available here: cidated. Only two of the selected regions (localised on BTA 14 at 24.4±25.1 Mbp and on https://doi.org/10.1371/journal.pone.0242200 BTA 16 at 42.5±43.5 Mb) overlapped in Yaroslavl, Kholmogor and Holstein breeds. In addi- Copyright: © 2020 Zinovieva et al. This is an open tion, we detected three novel selection sweeps in the genome of Yaroslavl (BTA 4 at 4.74± access article distributed under the terms of the 5.36 Mbp, BTA 15 at 17.80±18.77 Mbp, and BTA 17 at 45.59±45.61 Mbp) and Kholmogor Creative Commons Attribution License, which breeds (BTA 12 at 82.40±81.69 Mbp, BTA 15 at 16.04±16.62 Mbp, and BTA 18 at 0.19± permits unrestricted use, distribution, and reproduction in any medium, provided the original 1.46 Mbp) by using at least two of the above-mentioned methods. We expanded the list of author and source are credited. candidate genes associated with the selected genomic regions and performed their func- Data Availability Statement: We deposited our tional annotation. We discussed the possible involvement of the identified candidate genes Dataset files in the Dryad Digital Repository. in artificial selection in connection with the origin and development of the breeds. Our Zinovieva, Natalia et al. (2020), Selection PLOS ONE | https://doi.org/10.1371/journal.pone.0242200 November 16, 2020 1 / 30 PLOS ONE Selection signatures in native cattle breeds signatures in two oldest Russian native cattle findings on the Yaroslavl and Kholmogor breeds obtained using high-density SNP genotyp- breeds revealed using high-density single ing and three different statistical methods allowed the detection of novel putative genomic nucleotide polymorphism analysis, Dryad, Dataset, https://doi.org/10.5061/dryad.vt4b8gtq9. regions and candidate genes that might be under selection. These results might be useful for the sustainable development and conservation of these two oldest Russian native cattle Funding: This work was supported by the Russian Science Foundation within Project No. 19-76- breeds. 20012 (SNP genotyping) and the Russian Ministry of Science and Higher Education within theme 0445-2019-0024 (DNA collection and partly SNP genotyping). The URLshttp://grant.rscf.ru. Grant receiver no. 19-76-20012 is Zinovieva NA. The Introduction https://minobrnauki.gov.ru. Theme supervisor is National livestock genetic resources are the most important carriers of the unique forms of Dotsev A.V. The funder had no role in study design, data collection and analysis, decision to publish, or variability; they are necessary to ensure the sustainability of local agricultural production sys- preparation of the manuscript. tems [1]. In Russia, over a long period, various cattle breeds have formed, which are character- ised by good adaptation to the local environmental conditions and better suitability for the Competing interests: The authors have declared that no competing interests exist. development of geographic production systems [2]. Among the Black-and-White cattle breeds, Kholmogor and Yaroslavl dairy cattle have remarkable importance for animal husbandry in the Central and Northern regions of European Russia. Both breeds originated from small-stat- ure Great Russian Cattle (height at withers is 105±110 cm, body weight up to 325±390 kg [3, 4]. The first records of the presence of cattle on the islands in the upper reaches of the North- ern Dvina River near the Kholmogory town in Northern Russia date back to the sixteenth cen- tury (the breed was named after this town) [5]. Over a long history, the good pastures and hayfields in the Kholmogor breeding zone have contributed to the development of the tall cat- tle breed well suited for dairy production. In the 18th±19th centuries, the Kholmogor cattle were well-known in Russia and abroad owing to their high productivity and excellent quality of dairy products. Cattle breeding began to develop in the Yaroslavl region (near Moscow), based on which the breed is named, in the seventeenth and eighteenth centuries [5]. The Yaroslavl cattle were selected for adaptability, high feed efficiency and good reproductive ability even in poor forage conditions during win- ter. Moreover, this breed was in great demand among peasants and small cattle holders [4]. Most researchers suggested that foreign breeds, including Holsteins contributed little in the development of the Yaroslavl and Kholmogor cattle populations [6, 7], which was subse- quently confirmed by molecular genetics studies [8±10]. The studies of the historical speci- mens of Yaroslavl and Kholmogor cattle, dated from the end of 19th to the first half of 20th century using microsatellites, indicated that Russian breeds and Holsteins were developed from different ancestral populations [11]. In the 1960s, the number of Kholmogor and Yaro- slavl cattle was close to million individuals (993 and 951 thousand, respectively) each; in con- trast, in 2015, their census population size remarkably decreased to 222.9 and 50.5 thousand heads, respectively [12]. During the last decade, along with the remarkable decrease in popula- tion size, crossbreeding has been actively used in the remaining purebred animals, which could lead to the loss of genetic distinctness. Several molecular genetic studies have attempted to characterise the demographic history and population structure of the modern populations of Yaroslavl and Kholmogor breeds and their relationship to other taurine breeds [9, 10, 13, 14], but their results were, in some cases, controversial. By using microsatellite-based clustering, Li and Kantanen [13] suggested the composite origin of these breeds. Whole-genome studies performed using medium-density SNP chips showed that Yaroslavl and Kholmogor cattle are valuable national genetic resources, which have been little influenced by introgression with non-Russian breeds [9, 10]. The main- tenance of a visible part of historical components in the modern populations both of Yaroslavl and Kholmogor breeds was confirmed by the study of historical specimens [11]. Further PLOS ONE | https://doi.org/10.1371/journal.pone.0242200 November 16, 2020 2 / 30 PLOS ONE Selection signatures in native cattle breeds elucidation of the genetic architecture of these two breeds and more precise identification of genomic regions that are affected by putative selection may be achieved by using more power- ful molecular genetic tools such as bovine high-density SNP BeadChip (Illumina Inc., USA) which contains 777,962 SNPs. Several studies have explored the genome diversity and adaptation of cattle breeds by using high-density DNA arrays [15±17].
Recommended publications
  • PARSANA-DISSERTATION-2020.Pdf
    DECIPHERING TRANSCRIPTIONAL PATTERNS OF GENE REGULATION: A COMPUTATIONAL APPROACH by Princy Parsana A dissertation submitted to The Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland July, 2020 © 2020 Princy Parsana All rights reserved Abstract With rapid advancements in sequencing technology, we now have the ability to sequence the entire human genome, and to quantify expression of tens of thousands of genes from hundreds of individuals. This provides an extraordinary opportunity to learn phenotype relevant genomic patterns that can improve our understanding of molecular and cellular processes underlying a trait. The high dimensional nature of genomic data presents a range of computational and statistical challenges. This dissertation presents a compilation of projects that were driven by the motivation to efficiently capture gene regulatory patterns in the human transcriptome, while addressing statistical and computational challenges that accompany this data. We attempt to address two major difficulties in this domain: a) artifacts and noise in transcriptomic data, andb) limited statistical power. First, we present our work on investigating the effect of artifactual variation in gene expression data and its impact on trans-eQTL discovery. Here we performed an in-depth analysis of diverse pre-recorded covariates and latent confounders to understand their contribution to heterogeneity in gene expression measurements. Next, we discovered 673 trans-eQTLs across 16 human tissues using v6 data from the Genotype Tissue Expression (GTEx) project. Finally, we characterized two trait-associated trans-eQTLs; one in Skeletal Muscle and another in Thyroid. Second, we present a principal component based residualization method to correct gene expression measurements prior to reconstruction of co-expression networks.
    [Show full text]
  • Two Locus Inheritance of Non-Syndromic Midline Craniosynostosis Via Rare SMAD6 and 4 Common BMP2 Alleles 5 6 Andrew T
    1 2 3 Two locus inheritance of non-syndromic midline craniosynostosis via rare SMAD6 and 4 common BMP2 alleles 5 6 Andrew T. Timberlake1-3, Jungmin Choi1,2, Samir Zaidi1,2, Qiongshi Lu4, Carol Nelson- 7 Williams1,2, Eric D. Brooks3, Kaya Bilguvar1,5, Irina Tikhonova5, Shrikant Mane1,5, Jenny F. 8 Yang3, Rajendra Sawh-Martinez3, Sarah Persing3, Elizabeth G. Zellner3, Erin Loring1,2,5, Carolyn 9 Chuang3, Amy Galm6, Peter W. Hashim3, Derek M. Steinbacher3, Michael L. DiLuna7, Charles 10 C. Duncan7, Kevin A. Pelphrey8, Hongyu Zhao4, John A. Persing3, Richard P. Lifton1,2,5,9 11 12 1Department of Genetics, Yale University School of Medicine, New Haven, CT, USA 13 2Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA 14 3Section of Plastic and Reconstructive Surgery, Department of Surgery, Yale University School of Medicine, New Haven, CT, USA 15 4Department of Biostatistics, Yale University School of Medicine, New Haven, CT, USA 16 5Yale Center for Genome Analysis, New Haven, CT, USA 17 6Craniosynostosis and Positional Plagiocephaly Support, New York, NY, USA 18 7Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA 19 8Child Study Center, Yale University School of Medicine, New Haven, CT, USA 20 9The Rockefeller University, New York, NY, USA 21 22 ABSTRACT 23 Premature fusion of the cranial sutures (craniosynostosis), affecting 1 in 2,000 24 newborns, is treated surgically in infancy to prevent adverse neurologic outcomes. To 25 identify mutations contributing to common non-syndromic midline (sagittal and metopic) 26 craniosynostosis, we performed exome sequencing of 132 parent-offspring trios and 59 27 additional probands.
    [Show full text]
  • Genetic Determinants Underlying Rare Diseases Identified Using Next-Generation Sequencing Technologies
    Western University Scholarship@Western Electronic Thesis and Dissertation Repository 8-2-2018 1:30 PM Genetic determinants underlying rare diseases identified using next-generation sequencing technologies Rosettia Ho The University of Western Ontario Supervisor Hegele, Robert A. The University of Western Ontario Graduate Program in Biochemistry A thesis submitted in partial fulfillment of the equirr ements for the degree in Master of Science © Rosettia Ho 2018 Follow this and additional works at: https://ir.lib.uwo.ca/etd Part of the Medical Genetics Commons Recommended Citation Ho, Rosettia, "Genetic determinants underlying rare diseases identified using next-generation sequencing technologies" (2018). Electronic Thesis and Dissertation Repository. 5497. https://ir.lib.uwo.ca/etd/5497 This Dissertation/Thesis is brought to you for free and open access by Scholarship@Western. It has been accepted for inclusion in Electronic Thesis and Dissertation Repository by an authorized administrator of Scholarship@Western. For more information, please contact [email protected]. Abstract Rare disorders affect less than one in 2000 individuals, placing a huge burden on individuals, families and the health care system. Gene discovery is the starting point in understanding the molecular mechanisms underlying these diseases. The advent of next- generation sequencing has accelerated discovery of disease-causing genetic variants and is showing numerous benefits for research and medicine. I describe the application of next-generation sequencing, namely LipidSeq™ ‒ a targeted resequencing panel for the identification of dyslipidemia-associated variants ‒ and whole-exome sequencing, to identify genetic determinants of several rare diseases. Utilization of next-generation sequencing plus associated bioinformatics led to the discovery of disease-associated variants for 71 patients with lipodystrophy, two with early-onset obesity, and families with brachydactyly, cerebral atrophy, microcephaly-ichthyosis, and widow’s peak syndrome.
    [Show full text]
  • Identification and Characterization of Tissue-Resident Memory T Cells in Humans Brahma Vencel Kumar
    Identification and characterization of tissue-resident memory T cells in humans Brahma Vencel Kumar Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy under the Executive Committee of the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2018 ©2017 Brahma Vencel Kumar All rights reserved ABSTRACT Identification and characterization of tissue-resident memory T cells in humans Brahma Vencel Kumar Memory T cells are critical for maintaining lifelong immunity by protecting against reinfection with previously encountered pathogens. In recent years, a subset of memory T cells termed tissue-resident memory T cells (TRM) has emerged as the primary mediator of protection at many tissue sites. Numerous studies in mice have demonstrated that TRM accelerate pathogen clearance compared with other subsets of memory T cells. The defining characteristic of TRM is that they are retained within tissues and do not circulate in the blood. The lack of TRM in blood has proved to be a barrier for investigating the role of TRM in healthy humans. As a result, there are many outstanding questions about TRM biology in humans, including which phenotypic markers identify TRM, if TRM represent a unique memory subset, as well as defining transcriptional and functional characteristics of this subset. Through a unique collaboration with the local organ procurement agency, we obtained samples from >15 tissue sites from healthy organ donors of all ages. We found that the surface marker CD69 was expressed by memory CD4 + and CD8 + T cells in multiple tissues including spleen and other lymphoid tissues, lung, and intestines, but not in blood, suggesting that this marker may identify TRM in human tissues.
    [Show full text]
  • Cellular and Molecular Signatures in the Disease Tissue of Early
    Cellular and Molecular Signatures in the Disease Tissue of Early Rheumatoid Arthritis Stratify Clinical Response to csDMARD-Therapy and Predict Radiographic Progression Frances Humby1,* Myles Lewis1,* Nandhini Ramamoorthi2, Jason Hackney3, Michael Barnes1, Michele Bombardieri1, Francesca Setiadi2, Stephen Kelly1, Fabiola Bene1, Maria di Cicco1, Sudeh Riahi1, Vidalba Rocher-Ros1, Nora Ng1, Ilias Lazorou1, Rebecca E. Hands1, Desiree van der Heijde4, Robert Landewé5, Annette van der Helm-van Mil4, Alberto Cauli6, Iain B. McInnes7, Christopher D. Buckley8, Ernest Choy9, Peter Taylor10, Michael J. Townsend2 & Costantino Pitzalis1 1Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. Departments of 2Biomarker Discovery OMNI, 3Bioinformatics and Computational Biology, Genentech Research and Early Development, South San Francisco, California 94080 USA 4Department of Rheumatology, Leiden University Medical Center, The Netherlands 5Department of Clinical Immunology & Rheumatology, Amsterdam Rheumatology & Immunology Center, Amsterdam, The Netherlands 6Rheumatology Unit, Department of Medical Sciences, Policlinico of the University of Cagliari, Cagliari, Italy 7Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK 8Rheumatology Research Group, Institute of Inflammation and Ageing (IIA), University of Birmingham, Birmingham B15 2WB, UK 9Institute of
    [Show full text]
  • 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
    [Show full text]
  • A Review of the Recent Advances Made with SIRT6 and Its Implications on Aging Related Processes, Major Human Diseases, and Possible Therapeutic Targets
    biomolecules Review A Review of the Recent Advances Made with SIRT6 and its Implications on Aging Related Processes, Major Human Diseases, and Possible Therapeutic Targets Rubayat Islam Khan †, Saif Shahriar Rahman Nirzhor † and Raushanara Akter * Department of Pharmacy, BRAC University, 1212 Dhaka, Bangladesh; [email protected] (R.I.K.); [email protected] (S.S.R.N.) * Correspondence: [email protected]; Tel.: +880-179-8321-273 † These authors contributed equally to this work. Received: 10 June 2018; Accepted: 26 June 2018; Published: 29 June 2018 Abstract: Sirtuin 6 (SIRT6) is a nicotinamide adenine dinucleotide+ (NAD+) dependent enzyme and stress response protein that has sparked the curiosity of many researchers in different branches of the biomedical sciences. A unique member of the known Sirtuin family, SIRT6 has several different functions in multiple different molecular pathways related to DNA repair, glycolysis, gluconeogenesis, tumorigenesis, neurodegeneration, cardiac hypertrophic responses, and more. Only in recent times, however, did the potential usefulness of SIRT6 come to light as we learned more about its biochemical activity, regulation, biological roles, and structure Frye (2000). Even until very recently, SIRT6 was known more for chromatin signaling but, being a nascent topic of study, more information has been ascertained and its potential involvement in major human diseases including diabetes, cancer, neurodegenerative diseases, and heart disease. It is pivotal to explore the mechanistic workings
    [Show full text]
  • Gene Ontology Functional Annotations and Pleiotropy
    Network based analysis of genetic disease associations Sarah Gilman Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy under the Executive Committee of the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2014 © 2013 Sarah Gilman All Rights Reserved ABSTRACT Network based analysis of genetic disease associations Sarah Gilman Despite extensive efforts and many promising early findings, genome-wide association studies have explained only a small fraction of the genetic factors contributing to common human diseases. There are many theories about where this “missing heritability” might lie, but increasingly the prevailing view is that common variants, the target of GWAS, are not solely responsible for susceptibility to common diseases and a substantial portion of human disease risk will be found among rare variants. Relatively new, such variants have not been subject to purifying selection, and therefore may be particularly pertinent for neuropsychiatric disorders and other diseases with greatly reduced fecundity. Recently, several researchers have made great progress towards uncovering the genetics behind autism and schizophrenia. By sequencing families, they have found hundreds of de novo variants occurring only in affected individuals, both large structural copy number variants and single nucleotide variants. Despite studying large cohorts there has been little recurrence among the genes implicated suggesting that many hundreds of genes may underlie these complex phenotypes. The question
    [Show full text]
  • Open Data for Differential Network Analysis in Glioma
    International Journal of Molecular Sciences Article Open Data for Differential Network Analysis in Glioma , Claire Jean-Quartier * y , Fleur Jeanquartier y and Andreas Holzinger Holzinger Group HCI-KDD, Institute for Medical Informatics, Statistics and Documentation, Medical University Graz, Auenbruggerplatz 2/V, 8036 Graz, Austria; [email protected] (F.J.); [email protected] (A.H.) * Correspondence: [email protected] These authors contributed equally to this work. y Received: 27 October 2019; Accepted: 3 January 2020; Published: 15 January 2020 Abstract: The complexity of cancer diseases demands bioinformatic techniques and translational research based on big data and personalized medicine. Open data enables researchers to accelerate cancer studies, save resources and foster collaboration. Several tools and programming approaches are available for analyzing data, including annotation, clustering, comparison and extrapolation, merging, enrichment, functional association and statistics. We exploit openly available data via cancer gene expression analysis, we apply refinement as well as enrichment analysis via gene ontology and conclude with graph-based visualization of involved protein interaction networks as a basis for signaling. The different databases allowed for the construction of huge networks or specified ones consisting of high-confidence interactions only. Several genes associated to glioma were isolated via a network analysis from top hub nodes as well as from an outlier analysis. The latter approach highlights a mitogen-activated protein kinase next to a member of histondeacetylases and a protein phosphatase as genes uncommonly associated with glioma. Cluster analysis from top hub nodes lists several identified glioma-associated gene products to function within protein complexes, including epidermal growth factors as well as cell cycle proteins or RAS proto-oncogenes.
    [Show full text]
  • Cell Migration: How Neutrophils Set Their Compass
    RESEARCH HIGHLIGHTS IN BRIEF CELL MIGRATION How neutrophils set their compass Sustained directionality is an essential component of successful chemotaxis. Here, the authors show that the G protein Gαi and the mammalian homologue of the Drosophila melanogaster polarity protein Inscuteable (known as MINSC) are important for the maintenance of polarity and directionality during neutrophil chemotaxis. They observed that Gαi (which is released from Gβγ following ligand binding) accumulates at the leading edge of the cell. Gαi interacts directly with AGS3 or LGN, which themselves are bound to MINSC, recruiting it to this part of the cell. Moreover, MINSC is bound to the polarity complex PAR3–PAR6– aPKC, and this interaction targets the complex to the leading edge, thus establishing polarity. Notably, MINSC-deficient neutrophils, or neutrophils in which aPKC was blocked, showed normal motility but lacked directionality in their chemotaxis. ORIGINAL RESEARCH PAPER Kamakura, S. et al. The cell polarity protein mInsc regulates neutrophil chemotaxis via a noncanonical G protein signaling pathway. Dev. Cell http://dx.doi.org/10.1016/j.devcel.2013.06.008 (2013) DNA DAMAGE Facilitating repair The repair of DNA double-strand breaks (DSBs) can be hindered by the inability of repair factors to access damage sites in the tightly packaged chromatin. This study identifies a key role for the deacetylase sirtuin 6 (SIRT6) in facilitating chromatin relaxation and promoting repair. Toiber et al. observed that SIRT6 is rapidly recruited to DSBs, with much faster kinetics than previously reported. SIRT6 was shown to target the chromatin remodelling factor SNF2H to these sites and accelerate its association with them, as well as to deacetylate histone 3 at Lys56 (H3K56), which was required for SNF2H-mediated chromatin relaxation.
    [Show full text]
  • PTK6 Inhibition Promotes Apoptosis of Lapatinib-Resistant Her2+ Breast
    Park et al. Breast Cancer Research (2015) 17:86 DOI 10.1186/s13058-015-0594-z RESEARCH ARTICLE Open Access PTK6 inhibition promotes apoptosis of Lapatinib-resistant Her2+ breast cancer cells by inducing Bim Sun Hee Park1, Koichi Ito1, William Olcott1, Igor Katsyv1, Gwyneth Halstead-Nussloch1 and Hanna Y. Irie1,2* Abstract Introduction: Protein tyrosine kinase 6 (PTK6) is a non-receptor tyrosine kinase that is highly expressed in Human Epidermal Growth Factor 2+ (Her2+) breast cancers. Overexpression of PTK6 enhances anchorage-independent survival, proliferation, and migration of breast cancer cells. We hypothesized that PTK6 inhibition is an effective strategy to inhibit growth and survival of Her2+ breast cancer cells, including those that are relatively resistant to Lapatinib, a targeted therapy for Her2+ breast cancer, either intrinsically or acquired after continuous drug exposure. Methods: To determine the effects of PTK6 inhibition on Lapatinib-resistant Her2+ breast cancer cell lines (UACC893R1 and MDA-MB-453), we used short hairpin ribonucleic acid (shRNA) vectors to downregulate PTK6 expression. We determined the effects of PTK6 downregulation on growth and survival in vitro and in vivo, as well as the mechanisms responsible for these effects. Results: Lapatinib treatment of “sensitive” Her2+ cells induces apoptotic cell death and enhances transcript and protein levels of Bim, a pro-apoptotic Bcl2 family member. In contrast, treatment of relatively “resistant” Her2+ cells fails to induce Bim or enhance levels of cleaved, poly-ADP ribose polymerase (PARP). Downregulation of PTK6 expression in these “resistant” cells enhances Bim expression, resulting in apoptotic cell death. PTK6 downregulation impairs growth of these cells in in vitro 3-D MatrigelTM cultures, and also inhibits growth of Her2+ primary tumor xenografts.
    [Show full text]
  • Potential Role Vasculogenesis in Lupus Are Mediated
    Downloaded from http://www.jimmunol.org/ by guest on September 28, 2021 Kaplan is online at: on α average * The Journal of Immunology published online 30 August 2010 from submission to initial decision 4 weeks from acceptance to publication The Detrimental Effects of IFN- http://www.jimmunol.org/content/early/2010/08/30/jimmun ol.1001782 Vasculogenesis in Lupus Are Mediated by Repression of IL-1 Pathways: Potential Role in Atherogenesis and Renal Vascular Rarefaction J Immunol Seth G. Thacker, Celine C. Berthier, Deborah Mattinzoli, Maria Pia Rastaldi, Matthias Kretzler and Mariana J. Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html http://www.jimmunol.org/content/suppl/2010/08/30/jimmunol.100178 2.DC1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 28, 2021. Published August 30, 2010, doi:10.4049/jimmunol.1001782 The Journal of Immunology The Detrimental Effects of IFN-a on Vasculogenesis in Lupus Are Mediated by Repression of IL-1 Pathways: Potential Role in Atherogenesis and Renal Vascular Rarefaction Seth G. Thacker,*,1 Celine C. Berthier,†,1 Deborah Mattinzoli,‡ Maria Pia Rastaldi,‡ Matthias Kretzler,† and Mariana J.
    [Show full text]