DOCSLIB.ORG

Highly Interacting Regions of the Human Genome Are Enriched With

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Highly Interacting Regions of the Human Genome Are Enriched With www.nature.com/scientificreports OPEN Highly interacting regions of the human genome are enriched with enhancers and bound by DNA Received: 24 July 2018 Accepted: 12 February 2019 repair proteins Published: xx xx xxxx Haitham Sobhy 1, Rajendra Kumar 2,3, Jacob Lewerentz1, Ludvig Lizana2,3 & Per Stenberg4,5 In specifc cases, chromatin clearly forms long-range loops that place distant regulatory elements in close proximity to transcription start sites, but we have limited understanding of many loops identifed by Chromosome Conformation Capture (such as Hi-C) analyses. In eforts to elucidate their characteristics and functions, we have identifed highly interacting regions (HIRs) using intra- chromosomal Hi-C datasets with a new computational method based on looking at the eigenvector that corresponds to the smallest eigenvalue (here unity). Analysis of these regions using ENCODE data shows that they are in general enriched in bound factors involved in DNA damage repair and have actively transcribed genes. However, both highly transcribed regions as well as transcriptionally inactive regions can form HIRs. The results also indicate that enhancers and super-enhancers in particular form long-range interactions within the same chromosome. The accumulation of DNA repair factors in most identifed HIRs suggests that protection from DNA damage in these regions is essential for avoidance of detrimental rearrangements. Te chromatin in eukaryotic cells is not randomly organized, as various domains have been shown to occupy distinct ‘territories’ within the nucleus1–4. To decipher the chromatin architecture and three-dimensional (3D) organization within the nucleus, chromosome conformation capture techniques (such as 3C, 4C, 5C and Hi-C) have been developed5–7. In these techniques, chromatin segments in close spatial proximity are crosslinked, the crosslinked chromatin is digested and ligated, then the DNA is purifed and sequenced. Te chromatin segments identifed as being in close physical proximity in this manner are considered as interacting loci. Finally, fre- quencies of interactions between pairs of loci are quantifed. Visualization of chromosome conformation data as heat maps has revealed that the genome is partitioned into 3D compartments, inter alia topological associated domains (TADs) and A/B compartments8–10. Loci located within such domains tend to interact highly with each other and TADs’ boundaries are reportedly enriched in insulators and highly expressed genes8,9,11–13. It has also been observed in other types of experiments that distant regions of the genome can interact14, and there are observations indicating that expressed genes tend to co-localize in the nucleus, forming so called tran- scription factories5,15–18. In Drosophila it has been shown that Polycomb repressed regions can also co-localize in foci5,13,19–21. In addition, DNA double strand breaks, were shown through fuorescence labelling to travel within the nucleus22 and breaks have also been shown to cluster together23. Teoretically, there are obvious advantages in moving genomic regions that require similar factors into close three-dimensional proximity. However, bringing distant regions of the genome into proximity strongly raises risks of detrimental rearrangements if any DNA damage that occurs in such regions is not quickly repaired. Accordingly, there are indications that chromosomal rearrangements tend to occur in regions that are brought into three-dimensional proximity24. 1Department of Molecular Biology, Umeå University, Umeå, Sweden. 2Integrated Science Lab, Umeå University, Umeå, Sweden. 3Department of Physics, Umeå University, Umeå, Sweden. 4Division of CBRN Security and Defence, FOI–Swedish Defence Research Agency, Umeå, Sweden. 5Department of Ecology and Environmental Science (EMG), Umeå University, Umeå, Sweden. Correspondence and requests for materials should be addressed to H.S. (email: [email protected]) or L.L. (email: [email protected]) or P.S. (email: [email protected]) SCIENTIFIC REPORTS | (2019) 9:4577 | https://doi.org/10.1038/s41598-019-40770-9 1 www.nature.com/scientificreports/ www.nature.com/scientificreports Tus, the functional advantages of long-range interactions and associated 3-D conformations of DNA presum- ably outweigh the selective disadvantages of such risks. However, despite the eforts summarized above, knowl- edge of the nature and functions of many of the interactions is still rudimentary. Terefore, the aims of this study were to computationally defne regions of the genome that form high numbers of long-range intra-chromosomal contacts using Hi-C data and investigate their properties using ENCODE data. For this purpose, we developed a new method to transform two-dimensional Hi-C contact maps into one-dimensional profles. Tis method difers from TAD and A/B-fnding techniques involving the construction of correlation matrices then fnding clusters with Principal Component Analysis (PCA)25. Instead, our method involves direct use of Hi-C data (afer a simple element-wise manipulation), and extraction of the eigenvector for the smallest eigenvalue (here, unity), where the values are proportional to the interactivity (or number of contacts) for a particular genomic region. Using this method, we fnd that in line with previous observations some regions cluster by functions such as active transcription and Polycomb repression. In addition, we fnd that predicted enhancers and super-enhancers are potentially involved in long-range interactions and interestingly that most genomic regions with a high num- ber of contacts are bound by DNA damage repair factors. Material and Methods Stationary distribution. To calculate the interactivity (or numbers of contacts) of genomic regions we con- sider each chromatin segment as a node in a network. Te segment’s length is determined by the resolution of the Hi-C map, which thus also governs the numbers of nodes and links in the network. Te links represent physical interactions. Since these interactions are not uniform across the genome, we assign weights to the links that are proportional to the frequencies that pairs of chromatin segments are physically close to each other in a cell population. We restrict the analysis to intra-chromosomal contacts (i.e. contacts within the same chromosome), since data on inter-chromosomal contacts in Hi-C are too sparse to include. Te raw frequencies produced from a cell population could be directly taken as weights. However, contact frequency decays as a function of distance between chromatin loci, and contact frequencies are higher for neighbouring loci than for distant loci. Terefore, we derive weights from the raw Hi-C maps by subtracting each contact frequency with expected contact fre- quency, defned as the median contact frequency at each particular distance (Supplementary Information SI-1, 2 and Fig. S1). In the study reported here, Hi-C maps for GM12878 human lymphoblastoid cells at two resolutions (100 and 5 kb) were downloaded from the GEO database7. Next, we transformed the raw maps to ‘observed – expected’ maps using the gcMapExplorer package26 (https://github.com/rjdkmr/gcMapExplorer). From the ‘observed – expected’ map, we construct a transition probability matrix W, where every entry is the probability to jump from one node to any other node in the network. To calculate W, we divide every row in the ‘observed – expected’ map by its sum (shown as a network in Fig. S1 and Supplementary Information SI-2). Based on W, we then formulate a Markov model for how a particle randomly jumps between nodes in the network. Denoting Pn12(),(Pn), ...,(PnN ) as the probability that the particle is in node 1,2, …N at time n, we calculate Pn12(1++), Pn(1), ...,(PnN + 1) as a simple one-step process. pn(1+=)(pn),W where pn()= [(Pn12), Pn(),,... PnN()] From this, we are interested in the stationary probability distribution p()np=∞ = ∞, which we obtain from the equation p∞∞= pW. Tis means that p∞ is the normalised eigenvector of W associated with the eigenvalue one. In this study, to calculate p∞ we used the Scipy Python library to eigendecompose the transition probability matrix W, and extracted the eigenvector with the largest eigenvalue (one in this case). Te above method is imple- mented in the gcMapExplorer package26 (https://github.com/rjdkmr/gcMapExplorer), and the user can easily calculate the stationary distribution from a raw Hi-C map in a few steps. When the raw Hi-C map was directly used to calculate the Transition Probability Matrix (TPM), the dynamic range in the resulting stationary probability distribution (SPD) was limited due to the inclusion of both expected neighbouring and short-range contacts as well as long-range contacts (Fig. S2). Observed/expected’ normaliza- tion did not improve the dynamic range of the resulting SPD. When ‘observed-expected’ normalization was used to calculate the TPM, the SPD had a very similar profle but larger dynamic range (Fig. S2), thus it was applied in further analyses. Chromatin-related datasets and correlation. We downloaded ChIP-seq data for 177 chromatin-related datasets (available for GM12878 cells) from the ENCODE project website (https://www.encodeproject.org/), last updated in 2016. Te ENCODE dataset contains ChIP-seq data for 87 chromatin-bound proteins (listed in SI-3), as well as various histone modifcations, CG methylation, DNA accessibility (DNase-seq) and nucleosome den- sity (MNase-seq), hereafer ENCODE factors (177 in total). We used these data to calculate global correlations between
Load more

Recommended publications
  • Regulation of DNA Cross-Link Repair by the Fanconi Anemia/BRCA Pathway
    Downloaded from genesdev.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Regulation of DNA cross-link repair by the Fanconi anemia/BRCA pathway Hyungjin Kim and Alan D. D’Andrea1 Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA The maintenance of genome stability is critical for sur- and quadradials, a phenotype widely used as a diagnostic vival, and its failure is often associated with tumorigen- test for FA. esis. The Fanconi anemia (FA) pathway is essential for At least 15 FA gene products constitute a common the repair of DNA interstrand cross-links (ICLs), and a DNA repair pathway, the FA pathway, which resolves germline defect in the pathway results in FA, a cancer ICLs encountered during replication (Fig. 1A). Specifi- predisposition syndrome driven by genome instability. cally, eight FA proteins (FANCA/B/C/E/F/G/L/M) form Central to this pathway is the monoubiquitination of a multisubunit ubiquitin E3 ligase complex, the FA core FANCD2, which coordinates multiple DNA repair activ- complex, which activates the monoubiquitination of ities required for the resolution of ICLs. Recent studies FANCD2 and FANCI after genotoxic stress or in S phase have demonstrated how the FA pathway coordinates three (Wang 2007). The FANCM subunit initiates the pathway critical DNA repair processes, including nucleolytic in- (Fig. 1B). It forms a heterodimeric complex with FAAP24 cision, translesion DNA synthesis (TLS), and homologous (FA-associated protein 24 kDa), and the complex resem- recombination (HR). Here, we review recent advances in bles an XPF–ERCC1 structure-specific endonuclease pair our understanding of the downstream ICL repair steps (Ciccia et al.
    [Show full text]
  • Checkpoint Defects Require WRNIP1 to Counteract R-Loop-Associated
    bioRxiv preprint doi: https://doi.org/10.1101/858761; this version posted November 29, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. CHECKPOINT DEFECTS REQUIRE WRNIP1 TO COUNTERACT R-LOOP- ASSOCIATED GENOMIC INSTABILITY Veronica Marabitti1, Giorgia Lillo1, Eva Malacaria1, Valentina Palermo1, Pietro Pichierri1 and Annapaola Franchitto1, * 1Department of Environment and Health, Section of Mechanisms Biomarkers and Models, Istituto Superiore di Sanita’, Viale Regina Elena 299, Rome, 00161, Italy * To whom correspondence should be addressed. Tel: +39 0649903042; Fax: +39 0649903650; Email: [email protected] Keywords: Werner syndrome, RECQ helicases, DNA repair, Replication stress 1 bioRxiv preprint doi: https://doi.org/10.1101/858761; this version posted November 29, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. ABSTRACT Conflicts between replication and transcription are common source of genome instability and many factors participate in prevention or removal of harmful R-loops. Here, we demonstrate that a WRNIP1-mediated response plays an important role in counteracting accumulation of aberrant R- loops. Using human cellular models with compromised ATR-dependent checkpoint activation, we show that WRNIP1 is stabilised in chromatin and is needed for maintaining genome integrity by mediating the ATM-dependent phosphorylation of CHK1.
    [Show full text]
  • 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.
    [Show full text]
  • Vertebrate WRNIP1 and BLM Are Required for Efficient Maintenance of Genome Stability
    Genes Genet. Syst. (2008) 83, p. 95–100 Vertebrate WRNIP1 and BLM are required for efficient maintenance of genome stability Tomoko Hayashi1, Masayuki Seki1*, Eri Inoue1, Akari Yoshimura1, Yumiko Kusa1, Shusuke Tada1 and Takemi Enomoto1,2 1Molecular Cell Biology Laboratory, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan 2Tohoku University 21st Century COE Program, “Comprehensive Research and Education Center for Planning of Drug Development and Clinical Evaluation,” Sendai, Miyagi 980-8578, Japan (Received 25 September 2007, accepted 15 November 2007) Bloom syndrome (BS) is rare autosomal recessive disorder associated with chro- mosomal instability. The gene responsible for BS, BLM, encodes a protein belonging to the RecQ helicase family. Disruptions of the SGS1 gene of Saccha- romyces cerevisiae, which encodes the RecQ helicase homologue in the budding yeast, causes accelerated aging, and this phenotype is enhanced by the disruption of MGS1, the budding yeast homologue for WRNIP1. To examine the functional relationship between RecQ and WRNIP1 in vertebrate cells, we generated and characterized wrnip1/blm cells derived from the chicken B-lymphocyte line DT40. wrnip1/blm cells showed an additive elevation of sister chromatid exchange (SCE), suggesting that both genes independently contribute to the suppression of excess SCE formation. The double mutants were more sensitive to DNA damage from camptothecin (CPT), but not to damage from methyl methanesulfonate, than either single mutant. This result suggests that WRNIP1 and BLM function inde- pendently to repair DNA or induce tolerance to the lesions induced by CPT. Key words: BLM, DT40, Mgs1, RecQ, WRN, WRNIP1 Five genes encoding RecQ helicase homologues have RecQL4 mutations result in RAPADILINO syndrome and been identified in human cells, three of which are the Baller-Gerold syndrome, suggesting that RecQL4 has mul- causative genes for Bloom syndrome (BS), Werner syn- tiple functions (Dietschy et al., 2007).
    [Show full text]
  • Elucidating the Role of WRNIP1 in the Protection of Stalled Replication Forks
    Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2018 Elucidating the role of WRNIP1 in the protection of stalled replication forks Porebski, Bartlomiej Abstract: DNA is the blueprint of life. It contains all the information necessary for the synthesis of proteins – the building blocks and workhorses of the cell. Maintenance of DNA in an unchanged state is therefore of utmost importance, since any mutations or loss of the information it holds may lead to catastrophic events, such as cell death or tumorigenesis. DNA needs to be faithfully copied with every cell division, which is an enormous task, given its size and importance. DNA replication is constantly challenged by endogenous and exogenous factors, which have the potential to stall or stop replication – such a circumstance is called replication stress. While cells have evolved a number of mechanisms to deal with replication stress, e.g. checkpoint signaling that halts the cell cycle, DNA repair pathways that remove obstacles or factors that stabilise stalled replication forks, persisting replication stress inevitably leads to genomic instability and tumorigenesis. Interestingly, cancer cells, due to their unrestricted proliferation, have elevated level of replication stress, which makes them more susceptible to anti-cancer therapies that exacerbate genomic instability. It is thus obvious that dissecting the events and mechanisms leading to and following replication stress is important from a basic science and clinical research point of view. Among the many aspects of replication stress, one that is gaining an increasing amount of attention is replication fork stability.
    [Show full text]
  • Roles of the Werner Syndrome Recq Helicase in DNA Replication
    dna repair 7 (2008) 1776–1786 available at www.sciencedirect.com journal homepage: www.elsevier.com/locate/dnarepair Mini-review Roles of the Werner syndrome RecQ helicase in DNA replication Julia M. Sidorova ∗ Department of Pathology, University of Washington, Seattle, WA 98195-7705, USA article info abstract Article history: Congenital deficiency in the WRN protein, a member of the human RecQ helicase family, Received 22 July 2008 gives rise to Werner syndrome, a genetic instability and cancer predisposition disorder with Accepted 23 July 2008 features of premature aging. Cellular roles of WRN are not fully elucidated. WRN has been Published on line 6 September 2008 implicated in telomere maintenance, homologous recombination, DNA repair, and other processes. Here I review the available data that directly address the role of WRN in preserv- Keywords: ing DNA integrity during replication and propose that WRN can function in coordinating Werner syndrome replication fork progression with replication stress-induced fork remodeling. I further dis- RecQ helicase cuss this role of WRN within the contexts of damage tolerance group of regulatory pathways, Human cell culture and redundancy and cooperation with other RecQ helicases. Replication stress Published by Elsevier B.V. Damage tolerance Contents 1. Introduction ................................................................................................................. 1777 1.1. Is S phase prolonged in WRN-deficient cells? ...................................................................... 1777 1.2. What is the mechanism of the S phase extension in the absence of WRN? ...................................... 1778 1.3. Are all forks equal when it comes to WRN? ........................................................................ 1779 1.4. A mechanistic model for WRN role in replication elongation ..................................................... 1779 1.5. WRN and damage tolerance pathways ............................................................................. 1781 1.6.
    [Show full text]
  • Congenital Diseases of DNA Replication: Clinical Phenotypes and Molecular Mechanisms
    International Journal of Molecular Sciences Review Congenital Diseases of DNA Replication: Clinical Phenotypes and Molecular Mechanisms Megan Schmit and Anja-Katrin Bielinsky * Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; [email protected] * Correspondence: [email protected] Abstract: Deoxyribonucleic acid (DNA) replication can be divided into three major steps: initiation, elongation and termination. Each time a human cell divides, these steps must be reiteratively carried out. Disruption of DNA replication can lead to genomic instability, with the accumulation of point mutations or larger chromosomal anomalies such as rearrangements. While cancer is the most common class of disease associated with genomic instability, several congenital diseases with dysfunctional DNA replication give rise to similar DNA alterations. In this review, we discuss all congenital diseases that arise from pathogenic variants in essential replication genes across the spectrum of aberrant replisome assembly, origin activation and DNA synthesis. For each of these conditions, we describe their clinical phenotypes as well as molecular studies aimed at determining the functional mechanisms of disease, including the assessment of genomic stability. By comparing and contrasting these diseases, we hope to illuminate how the disruption of DNA replication at distinct steps affects human health in a surprisingly cell-type-specific manner. Keywords: Meier-Gorlin syndrome; natural killer cell deficiency; X-linked pigmentary reticulate disorder; Van Esch-O’Driscoll disease; IMAGe syndrome; FILS syndrome; Rothmund-Thomson syndrome; Baller-Gerold syndrome; RAPADILINO Citation: Schmit, M.; Bielinsky, A.-K. Congenital Diseases of DNA Replication: Clinical Phenotypes and 1. Introduction Molecular Mechanisms. Int. J. Mol. 1.1. Replication Initiation Sci.
    [Show full text]
  • Molecular Targeting and Enhancing Anticancer Efficacy of Oncolytic HSV-1 to Midkine Expressing Tumors
    University of Cincinnati Date: 12/20/2010 I, Arturo R Maldonado , hereby submit this original work as part of the requirements for the degree of Doctor of Philosophy in Developmental Biology. It is entitled: Molecular Targeting and Enhancing Anticancer Efficacy of Oncolytic HSV-1 to Midkine Expressing Tumors Student's name: Arturo R Maldonado This work and its defense approved by: Committee chair: Jeffrey Whitsett Committee member: Timothy Crombleholme, MD Committee member: Dan Wiginton, PhD Committee member: Rhonda Cardin, PhD Committee member: Tim Cripe 1297 Last Printed:1/11/2011 Document Of Defense Form Molecular Targeting and Enhancing Anticancer Efficacy of Oncolytic HSV-1 to Midkine Expressing Tumors A dissertation submitted to the Graduate School of the University of Cincinnati College of Medicine in partial fulfillment of the requirements for the degree of DOCTORATE OF PHILOSOPHY (PH.D.) in the Division of Molecular & Developmental Biology 2010 By Arturo Rafael Maldonado B.A., University of Miami, Coral Gables, Florida June 1993 M.D., New Jersey Medical School, Newark, New Jersey June 1999 Committee Chair: Jeffrey A. Whitsett, M.D. Advisor: Timothy M. Crombleholme, M.D. Timothy P. Cripe, M.D. Ph.D. Dan Wiginton, Ph.D. Rhonda D. Cardin, Ph.D. ABSTRACT Since 1999, cancer has surpassed heart disease as the number one cause of death in the US for people under the age of 85. Malignant Peripheral Nerve Sheath Tumor (MPNST), a common malignancy in patients with Neurofibromatosis, and colorectal cancer are midkine- producing tumors with high mortality rates. In vitro and preclinical xenograft models of MPNST were utilized in this dissertation to study the role of midkine (MDK), a tumor-specific gene over- expressed in these tumors and to test the efficacy of a MDK-transcriptionally targeted oncolytic HSV-1 (oHSV).
    [Show full text]
  • Potential of Data Integration to Identify Regulatory Snps in Late-Onset Alzheimer’S Disease GWAS Findings
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by D-Scholarship@Pitt Connecting the Dots: Potential of Data Integration to Identify Regulatory SNPs in Late-Onset Alzheimer’s Disease GWAS Findings Samantha L. Rosenthal1, M. Michael Barmada1, Xingbin Wang1, F. Yesim Demirci1, M. Ilyas Kamboh1,2* 1 Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America, 2 Alzheimer’s Disease Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America Abstract Late-onset Alzheimer’s disease (LOAD) is a multifactorial disorder with over twenty loci associated with disease risk. Given the number of genome-wide significant variants that fall outside of coding regions, it is possible that some of these variants alter some function of gene expression rather than tagging coding variants that alter protein structure and/or function. RegulomeDB is a database that annotates regulatory functions of genetic variants. In this study, we utilized RegulomeDB to investigate potential regulatory functions of lead single nucleotide polymorphisms (SNPs) identified in five genome-wide association studies (GWAS) of risk and age-at onset (AAO) of LOAD, as well as SNPs in LD (r2$0.80) with the lead GWAS SNPs. Of a total 614 SNPs examined, 394 returned RegulomeDB scores of 1–6. Of those 394 variants, 34 showed strong evidence of regulatory function (RegulomeDB score ,3), and only 3 of them were genome-wide significant SNPs (ZCWPW1/ rs1476679, CLU/rs1532278 and ABCA7/rs3764650). This study further supports the assumption that some of the non-coding GWAS SNPs are true associations rather than tagged associations and demonstrates the application of RegulomeDB to GWAS data.
    [Show full text]
  • RAD18, WRNIP1 and ATMIN Promote ATM Signalling in Response to Replication Stress
    Oncogene (2016) 35, 4009–4019 © 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 0950-9232/16 www.nature.com/onc ORIGINAL ARTICLE RAD18, WRNIP1 and ATMIN promote ATM signalling in response to replication stress This article has been corrected since Advance Online Publication and a corrigendum is also printed in this issue N Kanu1,8, T Zhang1,9, RA Burrell2, A Chakraborty1,11, J Cronshaw1, C DaCosta1, E Grönroos2, HN Pemberton3, E Anderton3, L Gonzalez4,10, S Sabbioneda5, HD Ulrich4,10, C Swanton2,6 and A Behrens1,7 The DNA replication machinery invariably encounters obstacles that slow replication fork progression, and threaten to prevent complete replication and faithful segregation of sister chromatids. The resulting replication stress activates ATR, the major kinase involved in resolving impaired DNA replication. In addition, replication stress also activates the related kinase ATM, which is required to prevent mitotic segregation errors. However, the molecular mechanism of ATM activation by replication stress is not defined. Here, we show that monoubiquitinated Proliferating Cell Nuclear Antigen (PCNA), a marker of stalled replication forks, interacts with the ATM cofactor ATMIN via WRN-interacting protein 1 (WRNIP1). ATMIN, WRNIP1 and RAD18, the E3 ligase responsible for PCNA monoubiquitination, are specifically required for ATM signalling and 53BP1 focus formation induced by replication stress, not ionising radiation. Thus, WRNIP1 connects PCNA monoubiquitination with ATMIN/ATM to activate ATM signalling in response to replication stress and contribute to the maintenance of genomic stability. Oncogene (2016) 35, 4009–4019; doi:10.1038/onc.2015.427; published online 9 November 2015 INTRODUCTION autophosphorylation,5,6 indicating that ATM is activated in response The ataxia telangiectasia mutated (ATM) kinase responds to the to replication stress.
    [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]
  • And Tetranucleotide Short Tandem Repeats N
    Nazaripanah et al. Human Genomics (2018) 12:17 https://doi.org/10.1186/s40246-018-0149-3 PRIMARYRESEARCH Open Access Genome-scale portrait and evolutionary significance of human-specific core promoter tri- and tetranucleotide short tandem repeats N. Nazaripanah1, F. Adelirad1, A. Delbari1, R. Sahaf1, T. Abbasi-Asl2 and M. Ohadi1* Abstract Background: While there is an ongoing trend to identify single nucleotide substitutions (SNSs) that are linked to inter/intra-species differences and disease phenotypes, short tandem repeats (STRs)/microsatellites may be of equal (if not more) importance in the above processes. Genes that contain STRs in their promoters have higher expression divergence compared to genes with fixed or no STRs in the gene promoters. In line with the above, recent reports indicate a role of repetitive sequences in the rise of young transcription start sites (TSSs) in human evolution. Results: Following a comparative genomics study of all human protein-coding genes annotated in the GeneCards database, here we provide a genome-scale portrait of human-specific short- and medium-size (≥ 3-repeats) tri- and tetranucleotide STRs and STR motifs in the critical core promoter region between − 120 and + 1 to the TSS and evidence of skewing of this compartment in reference to the STRs that are not human-specific (Levene’s test p <0. 001). Twenty-five percent and 26% enrichment of human-specific transcripts was detected in the tri and tetra human-specific compartments (mid-p < 0.00002 and mid-p < 0.002, respectively). Conclusion: Our findings provide the first evidence of genome-scale skewing of STRs at a specific region of the human genome and a link between a number of these STRs and TSS selection/transcript specificity.
    [Show full text]