DOCSLIB.ORG

Truncating Biallelic Variant in DNAJA1, Encoding the Co-Chaperone Hsp40, Is Associated with Intellectual Disability and Seizures

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Truncating Biallelic Variant in DNAJA1, Encoding the Co-Chaperone Hsp40, Is Associated with Intellectual Disability and Seizures neurogenetics (2019) 20:109–115 https://doi.org/10.1007/s10048-019-00573-6 SHORT COMMUNICATION Truncating biallelic variant in DNAJA1, encoding the co-chaperone Hsp40, is associated with intellectual disability and seizures Saud Alsahli1,2 & Ahmed Alfares3,4 & Francisco J. Guzmán-Vega5 & Stefan T. Arold5 & Duaa Ba-Armah2,6 & Fuad Al Mutairi2,7 Received: 20 November 2018 /Accepted: 14 March 2019 /Published online: 10 April 2019 # Springer-Verlag GmbH Germany, part of Springer Nature 2019 Abstract Intellectual disability poses a huge burden on the health care system, and it is one of the most common referral reasons to the genetic and child neurology clinic. Intellectual disability (ID) is genetically heterogeneous, and it is associated with several other neurological conditions. Exome sequencing is a robust genetic tool and has revolutionized the process of molecular diagnosis and novel gene discovery. Besides its diagnostic clinical value, novel gene discovery is prime in reverse genetics, when human mutations help to understand the function of a gene and may aid in better understanding of the human brain and nervous system. Using WES, we identified a biallelic truncating variant in DNAJA1 gene (c.511C>T p.(Gln171*) in a multiplex Saudi consan- guineous family. The main phenotype shared between the siblings was intellectual disability and seizure disorder. Keywords Intellectual disability . Seizure disorder . DNAJA1 . Exome sequencing . Chaperonopathy . Chaperone . Co-chaperone . Hsp40 Introduction genetics is the most likely culprit in the majority of cases even when the child lacks syndromic or other systemic features [2]. Intellectual disability (ID) is a neurodevelopmental disorder that Comparative genomic hybridization (CGH) is considered now is defined as an impairment in intellectual and adaptive func- the first-tier diagnostic test to order; nevertheless with the intro- tioning [1]. ID is a relatively common medical condition affect- duction of next-generation sequencing (NGS), many now are ing at least 1% of the general population, and it can result from advocating exome sequencing (WES) as the first-tier test [3]. myriad of causes [2]. ID can be generally classified based on WEShasshowntobecost-effectiveandledtoashorterdiag- other associated systemic findings as syndromic and nonsyn- nostic interval [4]. The diagnostic yield of NGS in CGH nega- dromic. ID is genetically heterogeneous, and the level of genet- tive syndromic and nonsyndromic ID has been reported as 68 ic involvement in ID has not thus far been elucidated; however, and 50%, respectively [2]. Several studies have demonstrated a Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10048-019-00573-6) contains supplementary material, which is available to authorized users. * Fuad Al Mutairi 4 Department of Pediatrics, Qassim University, Almulyda, [email protected] Buraydah, Saudi Arabia 5 Division of Biological and Environmental Sciences and Engineering 1 ’ Department of Pediatric Neurology, Texas Children s Hospital, (BESE), King Abdullah University of Science and Technology Baylor College of Medicine, Houston, TX, USA (KAUST), Computational Bioscience Research Center (CBRC), Thuwal 23955-6900, Saudi Arabia 2 King Abdullah International Medical Research Center (KAIMRC), 6 College of Medicine, King Saud bin Abdulaziz University for Health Department of Pediatrics, King Abdulaziz Medical City, Division of Sciences, Riyadh, Saudi Arabia Pediatric Neurology, Ministry of National Guard-Health Affairs (MNGHA), Riyadh, Saudi Arabia 3 Department of Pathology and Laboratory Medicine, King Abdulaziz 7 Division of Genetics, Department of Pediatrics, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs (MNGHA), Medical City, Ministry of National Guard-Health Affairs (MNGHA), Riyadh, Saudi Arabia Riyadh, Saudi Arabia 110 Neurogenetics (2019) 20:109–115 Fig. 1 Family pedigree of the current cohort high diagnostic yield in sequencing inbred populations that maturation and maintenance, and finally targeting of proteins reachedupto50%[2, 5–7]. More importantly, NGS has accel- for degradation through proteolytic processes of client pro- erated the process of novel gene discovery or candidate gene teins [11]. Herein, we show that a biallelic truncating variant proposal, and it led to an unprecedented expansion in the num- in DNAJA1 gene may cause ID and seizures in humans. berofgeneslinkedtoIDwithanestimatedmorethan2500 genes thus far [8]. Gene hunting in inbred populations is easier due to autozygosity mapping in multiplex families, which nar- Human subjects and method rows the field of search and ending a journey of diagnostic odyssey. Reaching for an accurate diagnosis is particularly im- Human subjects portant for inbred populations where autosomal recessive foun- der mutations make a relatively large fraction of the molecular Three siblings from a Saudi consanguineous family presented pool, and perhaps a preventable cause of ID and other to our practice. Their parents are a first-degree consanguine- neurodevelopmental disorders [9, 10]. ous couple with five healthy children (Fig. 1). All the affected DNAJA1 gene encodes a member of the DNAJ family of siblings underwent a clinical evaluation by neurologists and proteins, also known as heat shock protein 40 (Hsp40 or clinical geneticists. Our institution’s standardized clinical ex- Hsc40), which acts as co-chaperone for Hsp70 and Hsp90. ome consent was obtained from their parents, and the study DNAJ proteins are responsible for several essential cellular received ethical approval from King Abdullah International processes including folding polypeptide chains, modulate pro- Medical Research Center (KAIMRC). Additional informed tein assembly, disassembly, translocation through membranes consent was obtained from all individual participants for into cellular compartments, assist in conformational whom identifying information is included in this article. Neurogenetics (2019) 20:109–115 111 Table 1 Current cohort phenotype Patient 1 Patient 2 Patient 3 Age 14 years 16 years 25 years Onset of the symptoms 3 months as seizure 12 months as DD Early childhood as DD Seizures + + + Seizures age of onset 3 months 11 years 12 years Intellectual disability + + + Behavioral disorders – + – Dysmorphic features + + + • Round face + + + • Protruding ears + + + • Short neck + + + • Concave nail beds ++ + + + + BMI 29.2 44.7 38.1 Brain MRI Thickened corpus callosum NA Normal EEG Normal NA Normal Other findings Renal stone Gallbladder stone Cleft palate Deviated nasal septum and otitis media DD developmental delay, BMI body mass index, MRI magnetic resonance imaging, EEG electroencephalography, NA not available Molecular analysis Results Autozygome analysis The three affected siblings share a strikingly similar pheno- type, and they look phenotypically different from their unaf- Blood samples were collected from all affected individuals, the fected siblings. All of them are overweight, intellectually dis- parents, and two healthy siblings in EDTA tubes, and DNA was abled with a generalized tonic clonic seizure disorder, have extracted from whole blood. We started with whole-genome ar- moon facies, protruding ears, and short neck. Epilepsy gene ray-based comparative genomic hybridization (aCGH) and panel was negative (Table 1) (Fig. 3) (see Table S2 for a genome-wide single nucleotide polymorphism (SNP) for the af- detailed clinical synopsis). fected siblings and their parents as previously described [12]. We Initial filtering for intellectual disability and seizure disor- did not detect any significant copy number changes; however, it der variants revealed no mutations. All the affected siblings showed large regions of homozygosity between the affected sib- were homozygous for a truncating variant in DNAJA1 gene lings and their parents (Table S1). (NM_001539.3) c.511C>T p.(Gln171*)). We confirmed the variant by Sanger sequencing in all patients, and the variant segregated well in unaffected family members (Fig. 2). This Exome sequencing variant was absent as well as other truncating variants in a large-scale exome sequencing databases such as Exome We then proceeded with WES in all affected patients and their Aggregation Consortium (ExAC), dbSNP/1000 genome, or parents as previously described [13]. The generated library is Exome Sequencing Project (ESP) and in the Genome sequenced on an Illumina platform to obtain an average coverage Aggregation Database (gnomAD) databases. Also, this vari- depth of ~ 100×. Typically, ~ 97% of the targeted bases are cov- ant along with other truncating variants were absent from ered > 10×. An end-to-end in-house bioinformatic pipeline in- 2000 ethnically matched controls in local database and our cluding base calling, alignment of reads to GRCh37/hg19 ge- institute’s database Majeen (1200 exomes). nome assembly, primary filtering out of low-quality reads and probable artifacts, and subsequent annotation of variants was applied. Evaluation is focused on coding exons along with Structural and functional analysis flanking ± 20 intronic bases. All inheritance patterns were con- sidered. In addition, provided family history and clinical infor- DNAJA1 is composed of a N-terminal J-domain followed by mation were used to evaluate eventually identified variants. a G/F-rich region and two zinc finger motifs, which connect to 112 Neurogenetics (2019) 20:109–115 227 of the 397 protein residues. This truncation results in the loss of two of the CXXCXGXG
Load more

Recommended publications
  • Computational Genome-Wide Identification of Heat Shock Protein Genes in the Bovine Genome [Version 1; Peer Review: 2 Approved, 1 Approved with Reservations]
    F1000Research 2018, 7:1504 Last updated: 08 AUG 2021 RESEARCH ARTICLE Computational genome-wide identification of heat shock protein genes in the bovine genome [version 1; peer review: 2 approved, 1 approved with reservations] Oyeyemi O. Ajayi1,2, Sunday O. Peters3, Marcos De Donato2,4, Sunday O. Sowande5, Fidalis D.N. Mujibi6, Olanrewaju B. Morenikeji2,7, Bolaji N. Thomas 8, Matthew A. Adeleke 9, Ikhide G. Imumorin2,10,11 1Department of Animal Breeding and Genetics, Federal University of Agriculture, Abeokuta, Nigeria 2International Programs, College of Agriculture and Life Sciences, Cornell University, Ithaca, NY, 14853, USA 3Department of Animal Science, Berry College, Mount Berry, GA, 30149, USA 4Departamento Regional de Bioingenierias, Tecnologico de Monterrey, Escuela de Ingenieria y Ciencias, Queretaro, Mexico 5Department of Animal Production and Health, Federal University of Agriculture, Abeokuta, Nigeria 6Usomi Limited, Nairobi, Kenya 7Department of Animal Production and Health, Federal University of Technology, Akure, Nigeria 8Department of Biomedical Sciences, Rochester Institute of Technology, Rochester, NY, 14623, USA 9School of Life Sciences, University of KwaZulu-Natal, Durban, 4000, South Africa 10School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, 30032, USA 11African Institute of Bioscience Research and Training, Ibadan, Nigeria v1 First published: 20 Sep 2018, 7:1504 Open Peer Review https://doi.org/10.12688/f1000research.16058.1 Latest published: 20 Sep 2018, 7:1504 https://doi.org/10.12688/f1000research.16058.1 Reviewer Status Invited Reviewers Abstract Background: Heat shock proteins (HSPs) are molecular chaperones 1 2 3 known to bind and sequester client proteins under stress. Methods: To identify and better understand some of these proteins, version 1 we carried out a computational genome-wide survey of the bovine 20 Sep 2018 report report report genome.
    [Show full text]
  • Allele-Specific Silencing of Mutant Ataxin-7 in SCA7 Patient-Derived
    European Journal of Human Genetics (2014) 22, 1369–1375 & 2014 Macmillan Publishers Limited All rights reserved 1018-4813/14 www.nature.com/ejhg ARTICLE Allele-specific silencing of mutant Ataxin-7 in SCA7 patient-derived fibroblasts Janine Scholefield1,3, Lauren Watson1,2,3, Danielle Smith2, Jacquie Greenberg2 and Matthew JA Wood*,1,2 Polyglutamine (polyQ) disorders are inherited neurodegenerative conditions defined by a common pathogenic CAG repeat expansion leading to a toxic gain-of-function of the mutant protein. Consequences of this toxicity include activation of heat- shock proteins (HSPs), impairment of the ubiquitin-proteasome pathway and transcriptional dysregulation. Several studies in animal models have shown that reducing levels of toxic protein using small RNAs would be an ideal therapeutic approach for such disorders, including spinocerebellar ataxia-7 (SCA7). However, testing such RNA interference (RNAi) effectors in genetically appropriate patient cell lines with a disease-relevant phenotype has yet to be explored. Here, we have used primary adult dermal fibroblasts from SCA7 patients and controls to assess the endogenous allele-specific silencing of ataxin-7 by two distinct siRNAs. We further identified altered expression of two disease-relevant transcripts in SCA7 patient cells: a twofold increase in levels of the HSP DNAJA1 and a twofold decrease in levels of the de-ubiquitinating enzyme, UCHL1. After siRNA treatment, the expression of both genes was restored towards normal levels. To our knowledge, this is the first time that allele- specific silencing of mutant ataxin-7, targeting a common SNP, has been demonstrated in patient cells. These findings highlight the advantage of an allele-specific RNAi-based therapeutic approach, and indicate the value of primary patient-derived cells as useful models for mechanistic studies and for measuring efficacy of RNAi effectors on a patient-to-patient basis in the polyQ diseases.
    [Show full text]
  • Key Genes Regulating Skeletal Muscle Development and Growth in Farm Animals
    animals Review Key Genes Regulating Skeletal Muscle Development and Growth in Farm Animals Mohammadreza Mohammadabadi 1 , Farhad Bordbar 1,* , Just Jensen 2 , Min Du 3 and Wei Guo 4 1 Department of Animal Science, Faculty of Agriculture, Shahid Bahonar University of Kerman, Kerman 77951, Iran; [email protected] 2 Center for Quantitative Genetics and Genomics, Aarhus University, 8210 Aarhus, Denmark; [email protected] 3 Washington Center for Muscle Biology, Department of Animal Sciences, Washington State University, Pullman, WA 99163, USA; [email protected] 4 Muscle Biology and Animal Biologics, Animal and Dairy Science, University of Wisconsin-Madison, Madison, WI 53558, USA; [email protected] * Correspondence: [email protected] Simple Summary: Skeletal muscle mass is an important economic trait, and muscle development and growth is a crucial factor to supply enough meat for human consumption. Thus, understanding (candidate) genes regulating skeletal muscle development is crucial for understanding molecular genetic regulation of muscle growth and can be benefit the meat industry toward the goal of in- creasing meat yields. During the past years, significant progress has been made for understanding these mechanisms, and thus, we decided to write a comprehensive review covering regulators and (candidate) genes crucial for muscle development and growth in farm animals. Detection of these genes and factors increases our understanding of muscle growth and development and is a great help for breeders to satisfy demands for meat production on a global scale. Citation: Mohammadabadi, M.; Abstract: Farm-animal species play crucial roles in satisfying demands for meat on a global scale, Bordbar, F.; Jensen, J.; Du, M.; Guo, W.
    [Show full text]
  • Evaluation of the Role of Human Dnajas in the Response to Cytotoxic Chemotherapeutic Agents in a Yeast Model System
    Hindawi BioMed Research International Volume 2020, Article ID 9097638, 14 pages https://doi.org/10.1155/2020/9097638 Research Article Evaluation of the Role of Human DNAJAs in the Response to Cytotoxic Chemotherapeutic Agents in a Yeast Model System AurelliaWhitmore,DevonFreeny,SamanthaJ.Sojourner,JanaS.Miles,WillieM.Graham, and Hernan Flores-Rozas College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, USA Correspondence should be addressed to Hernan Flores-Rozas; hernan.fl[email protected] Received 25 September 2019; Revised 3 January 2020; Accepted 9 January 2020; Published 14 February 2020 Guest Editor: Chengsheng Wu Copyright © 2020 Aurellia Whitmore et al. -is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Heat-shock proteins (HSPs) play a crucial role in maintaining protein stability for cell survival during stress-induced insults. Overexpression of HSPs in cancer cells results in antiapoptotic activity contributing to cancer cell survival and restricting the efficacy of cytotoxic chemotherapy, which continues to play an important role in the treatment of many cancers, including triple- negative breast cancer (TNBC). First-line therapy for TNBC includes anthracycline antibiotics, which are associated with serious dose-dependent side effects and the development of resistance. We previously identified YDJ1, which encodes a heat-shock protein 40 (HSP40), as an important factor in the cellular response to anthracyclines in yeast, with mutants displaying over 100- fold increased sensitivity to doxorubicin. In humans, the DNAJA HSP40s are homologues of YDJ1. To determine the role of DNAJAs in the cellular response to cytotoxic drugs, we investigated their ability to rescue ydj1Δ mutants from exposure to chemotherapeutic agents.
    [Show full text]
  • The HSP70 Chaperone Machinery: J Proteins As Drivers of Functional Specificity
    REVIEWS The HSP70 chaperone machinery: J proteins as drivers of functional specificity Harm H. Kampinga* and Elizabeth A. Craig‡ Abstract | Heat shock 70 kDa proteins (HSP70s) are ubiquitous molecular chaperones that function in a myriad of biological processes, modulating polypeptide folding, degradation and translocation across membranes, and protein–protein interactions. This multitude of roles is not easily reconciled with the universality of the activity of HSP70s in ATP-dependent client protein-binding and release cycles. Much of the functional diversity of the HSP70s is driven by a diverse class of cofactors: J proteins. Often, multiple J proteins function with a single HSP70. Some target HSP70 activity to clients at precise locations in cells and others bind client proteins directly, thereby delivering specific clients to HSP70 and directly determining their fate. In their native cellular environment, polypeptides are participates in such diverse cellular functions. Their constantly at risk of attaining conformations that pre- functional diversity is remarkable considering that vent them from functioning properly and/or cause them within and across species, HSP70s have high sequence to aggregate into large, potentially cytotoxic complexes. identity. They share a single biochemical activity: an Molecular chaperones guide the conformation of proteins ATP-dependent client-binding and release cycle com- throughout their lifetime, preventing their aggregation bined with client protein recognition, which is typi- by protecting interactive surfaces against non-productive cally rather promiscuous. This apparent conundrum interactions. Through such inter actions, molecular chap- is resolved by the fact that HSP70s do not work alone, erones aid in the folding of nascent proteins as they are but rather as ‘HSP70 machines’, collaborating with synthesized by ribosomes, drive protein transport across and being regulated by several cofactors.
    [Show full text]
  • Senescence Inhibits the Chaperone Response to Thermal Stress
    SUPPLEMENTAL INFORMATION Senescence inhibits the chaperone response to thermal stress Jack Llewellyn1, 2, Venkatesh Mallikarjun1, 2, 3, Ellen Appleton1, 2, Maria Osipova1, 2, Hamish TJ Gilbert1, 2, Stephen M Richardson2, Simon J Hubbard4, 5 and Joe Swift1, 2, 5 (1) Wellcome Centre for Cell-Matrix Research, Oxford Road, Manchester, M13 9PT, UK. (2) Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, M13 9PL, UK. (3) Current address: Department of Biomedical Engineering, University of Virginia, Box 800759, Health System, Charlottesville, VA, 22903, USA. (4) Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, M13 9PL, UK. (5) Correspondence to SJH ([email protected]) or JS ([email protected]). Page 1 of 11 Supplemental Information: Llewellyn et al. Chaperone stress response in senescence CONTENTS Supplemental figures S1 – S5 … … … … … … … … 3 Supplemental table S6 … … … … … … … … 10 Supplemental references … … … … … … … … 11 Page 2 of 11 Supplemental Information: Llewellyn et al. Chaperone stress response in senescence SUPPLEMENTAL FIGURES Figure S1. A EP (passage 3) LP (passage 16) 200 µm 200 µm 1.5 3 B Mass spectrometry proteomics (n = 4) C mRNA (n = 4) D 100k EP 1.0 2 p < 0.0001 p < 0.0001 LP p < 0.0001 p < 0.0001 ) 0.5 1 2 p < 0.0001 p < 0.0001 10k 0.0 0 -0.5 -1 Cell area (µm Cell area fold change vs. EP fold change vs.
    [Show full text]
  • Characterization of the Dual Functional Effects of Heat Shock Proteins (Hsps
    Zhang et al. Genome Medicine (2020) 12:101 https://doi.org/10.1186/s13073-020-00795-6 RESEARCH Open Access Characterization of the dual functional effects of heat shock proteins (HSPs) in cancer hallmarks to aid development of HSP inhibitors Zhao Zhang1†, Ji Jing2†, Youqiong Ye1, Zhiao Chen1, Ying Jing1, Shengli Li1, Wei Hong1, Hang Ruan1, Yaoming Liu1, Qingsong Hu3, Jun Wang4, Wenbo Li1, Chunru Lin3, Lixia Diao5*, Yubin Zhou2* and Leng Han1* Abstract Background: Heat shock proteins (HSPs), a representative family of chaperone genes, play crucial roles in malignant progression and are pursued as attractive anti-cancer therapeutic targets. Despite tremendous efforts to develop anti-cancer drugs based on HSPs, no HSP inhibitors have thus far reached the milestone of FDA approval. There remains an unmet need to further understand the functional roles of HSPs in cancer. Methods: We constructed the network for HSPs across ~ 10,000 tumor samples from The Cancer Genome Atlas (TCGA) and ~ 10,000 normal samples from Genotype-Tissue Expression (GTEx), and compared the network disruption between tumor and normal samples. We then examined the associations between HSPs and cancer hallmarks and validated these associations from multiple independent high-throughput functional screens, including Project Achilles and DRIVE. Finally, we experimentally characterized the dual function effects of HSPs in tumor proliferation and metastasis. Results: We comprehensively analyzed the HSP expression landscape across multiple human cancers and revealed a global disruption of the co-expression network for HSPs. Through analyzing HSP expression alteration and its association with tumor proliferation and metastasis, we revealed dual functional effects of HSPs, in that they can simultaneously influence proliferation and metastasis in opposite directions.
    [Show full text]
  • Human Hsp40 Proteins, DNAJA1 and DNAJA2, As Potential Targets of the Immune Response Triggered by Bacterial Dnaj in Rheumatoid Arthritis
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Springer - Publisher Connector Cell Stress and Chaperones (2013) 18:653–659 DOI 10.1007/s12192-013-0407-1 SHORT COMMUNICATION Human Hsp40 proteins, DNAJA1 and DNAJA2, as potential targets of the immune response triggered by bacterial DnaJ in rheumatoid arthritis Agnieszka Kotlarz & Stefan Tukaj & Konrad Krzewski & Elzbieta Brycka & Barbara Lipinska Received: 11 December 2012 /Revised: 23 January 2013 /Accepted: 24 January 2013 /Published online: 14 February 2013 # The Author(s) 2013. This article is published with open access at Springerlink.com Abstract Hsp40 proteins of bacterial and human origin are DNAJA1 antibodies in the sera of RA patients. This finding suspected to be involved in the pathogenesis of rheumatoid supports the molecular mimicry hypothesis that human arthritis (RA). It has been shown that sera of RA patients Hsp40 could be the targets of antibodies originally directed contain increased levels of antibodies directed to bacterial against bacterial DnaJ in RA. and human Hsp40s. The aim of this work was to explore immunological similarities between the bacterial (DnaJ) and Keywords Anti-Hsp40 autoantibodies . Hsp40 in human (DNAJA1 and DNAJA2) Hsp40 proteins in relation rheumatoid arthritis . Cross-reactivity of anti-Hsp40 to their possible involvement in the RA. Using polyclonal antibodies . Anti-DNAJ monoclonal antibodies . Molecular antibodies directed against a full-length DnaJ or its domains, mimicry against DNAJA1 and DNAJA2, as well as monoclonal anti- DnaJ antibodies, we found immunological similarities be- tween the bacterial and human Hsp40s. Both ELISA and Introduction Western blotting showed that these similarities were not restricted to the conserved J domains but were also present Heat shock proteins (Hsps) are a family of evolutionarily in the C-terminal variable regions.
    [Show full text]
  • Integrative Approach Using Liver and Duodenum RNA-Seq Data Identifies
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE www.nature.com/scientificreportsprovided by IRTA Pubpro OPEN Integrative approach using liver and duodenum RNA-Seq data identifes candidate genes and pathways Received: 30 August 2017 Accepted: 21 December 2017 associated with feed efciency in Published: xx xx xxxx pigs Yuliaxis Ramayo-Caldas 1, Maria Ballester1, Juan Pablo Sánchez1, Olga González- Rodríguez1, Manuel Revilla 2,3, Henry Reyer4, Klaus Wimmers 4,5, David Torrallardona 6 & Raquel Quintanilla1 This study aims identifying candidate genes and pathways associated with feed efciency (FE) in pigs. Liver and duodenum transcriptomes of 37 gilts showing high and low residual feed intake (RFI) were analysed by RNA-Seq. Gene expression data was explored through diferential expression (DE) and weighted gene co-expression network analyses. DE analysis revealed 55 and 112 diferentially regulated genes in liver and duodenum tissues, respectively. Clustering genes according to their connectivity resulted in 23 (liver) and 25 (duodenum) modules of genes with a co-expression pattern. Four modules, one in liver (with 444 co-expressed genes) and three in duodenum (gathering 37, 126 and 41 co- expressed genes), were signifcantly associated with FE indicators. Intra-module analyses revealed tissue-specifc candidate genes; 12 of these genes were also identifed as DE between individuals with high and low RFI. Pathways enriched by the list of genes showing DE and/or belonging to FE co-expressed modules included response to oxidative stress, infammation, immune response, lipid metabolism and thermoregulation. Low overlapping between genes identifed in duodenum and liver tissues was observed but heat shock proteins were associated to FE in both tissues.
    [Show full text]
  • High Temperature Suppressed SSC Self-Renewal Through S Phase Cell Cycle Arrest but Not Apoptosis
    Wang et al. Stem Cell Research & Therapy (2019) 10:227 https://doi.org/10.1186/s13287-019-1335-5 RESEARCH Open Access High temperature suppressed SSC self- renewal through S phase cell cycle arrest but not apoptosis Jia Wang1†, Wei-Jun Gao1†, Shou-Long Deng2, Xiang Liu1, Hua Jia1,3* and Wen-Zhi Ma1,3* Abstract Background: High temperature has a very adverse effect on mammalian spermatogenesis and eventually leads to sub- or infertility through either apoptosis or DNA damage. However, the direct effects of heat stress on the development of spermatogonial stem cells (SSCs) are still unknown because SSCs are rare in the testes. Methods: In the present study, we first used in vitro-cultured SSCs to study the effect of heat shock treatment on SSC development. Then, we used RNA-Seq analysis to identify new genes or signalling pathways implicated in the heat stress response. Results: We found that 45 min of 43 °C heat shock treatment significantly inhibited the proliferation of SSCs 2 h after treatment but did not lead to apoptosis. In total, 17,822 genes were identified by RNA-Seq after SSC heat shock treatment. Among these genes, we found that 200 of them had significantly changed expression, with 173 upregulated and 27 downregulated genes. The number of differentially expressed genes in environmental information processing pathways was 37, which was the largest number. We screened the candidate JAK-STAT signalling pathway on the basis of inhibition of cell cycle progression and found that the JAK-STAT pathway was inhibited after heat shock treatment. The flow cytometry results further confirmed that heat stress caused S phase cycle arrest of SSCs.
    [Show full text]
  • Proteomic Profiling and Genome-Wide Mapping of O-Glcnac Chromatin
    ARTICLE https://doi.org/10.1038/s41467-020-19579-y OPEN Proteomic profiling and genome-wide mapping of O-GlcNAc chromatin-associated proteins reveal an O-GlcNAc-regulated genotoxic stress response Yubo Liu 1,3, Qiushi Chen 2,3, Nana Zhang1, Keren Zhang2, Tongyi Dou1, Yu Cao1, Yimin Liu1, Kun Li1, ✉ ✉ Xinya Hao1, Xueqin Xie1, Wenli Li1, Yan Ren 2 & Jianing Zhang 1 fi 1234567890():,; O-GlcNAc modi cation plays critical roles in regulating the stress response program and cellular homeostasis. However, systematic and multi-omics studies on the O-GlcNAc regu- lated mechanism have been limited. Here, comprehensive data are obtained by a chemical reporter-based method to survey O-GlcNAc function in human breast cancer cells stimulated with the genotoxic agent adriamycin. We identify 875 genotoxic stress-induced O-GlcNAc chromatin-associated proteins (OCPs), including 88 O-GlcNAc chromatin-associated tran- scription factors and cofactors (OCTFs), subsequently map their genomic loci, and construct a comprehensive transcriptional reprogramming network. Notably, genotoxicity-induced O- GlcNAc enhances the genome-wide interactions of OCPs with chromatin. The dynamic binding switch of hundreds of OCPs from enhancers to promoters is identified as a crucial feature in the specific transcriptional activation of genes involved in the adaptation of cancer cells to genotoxic stress. The OCTF nuclear factor erythroid 2-related factor-1 (NRF1) is found to be a key response regulator in O-GlcNAc-modulated cellular homeostasis. These results provide a valuable clue suggesting that OCPs act as stress sensors by regulating the expression of various genes to protect cancer cells from genotoxic stress.
    [Show full text]
  • Gene List HTG Edgeseq Oncology Biomarker Panel
    Gene List HTG EdgeSeq Oncology Biomarker Panel For Research Use Only. Not for use in diagnostic procedures. A2M ADRA2B APH1B BAG1 BRCA2 CARM1 CCNH CDC25A CHI3L1 COX7B CXCL16 DESI1 ABCA2 ADRA2C APOC2 BAG2 BRIP1 CASP1 CCNO CDC25B CHI3L2 CP CXCL2 DFFA ABCA3 AFF1 APOC4 BAG3 BTC CASP10 CCNT1 CDC25C CHMP4B CPT1A CXCL3 DHCR24 ABCA4 AGER APOL3 BAG4 BTG1 CASP12 CCR1 CDC34 CHPT1 CPT1B CXCL5 DHH ABCA5 AGFG1 APP BAG5 BTG2 CASP14 CCR10 CDC42 CHRNA1 CPT1C CXCL6 DHX58 ABCA9 AGGF1 APPBP2 BAI1 BTG3 CASP2 CCR2 CDC42BPA CHRNB1 CPT2 CXCL8 DIABLO ABCB11 AGT AQP1 BAIAP3 BTK CASP3 CCR3 CDC6 CHSY1 CRADD CXCL9 DIAPH3 ABCB4 AHNAK AQP2 BAK1 BTRC CASP4 CCR4 CDC7 CHUK CREB1 CXCR1 DICER1 ABCB5 AHNAK2 AQP4 BAMBI BUB1 CASP5 CCR5 CDCA7 CIC CREB3L1 CXCR2 DISP1 ABCB6 AHR AQP7 BAP1 BUB1B CASP6 CCR6 CDH1 CIDEA CREB3L3 CXCR3 DISP2 ABCC1 AHRR AQP9 BATF C17orf53 CASP7 CCR7 CDH13 CIDEB CREB3L4 CXCR4 DKC1 ABCC10 AICDA AR BAX C19orf40 CASP8 CCR8 CDH15 CIRBP CREB5 CXCR5 DKK1 ABCC11 AIFM1 ARAF BBC3 C1orf106 CASP8AP2 CCR9 CDH2 CITED2 CREBBP CXCR6 DKK2 ABCC12 AIMP2 AREG BBS4 C1orf159 CASP9 CCRL2 CDH3 CKB CRK CXXC4 DKK3 ABCC2 AK1 ARHGAP44 BCAR1 C1orf86 CAV1 CCS CDH5 CKLF CRLF2 CXXC5 DKK4 ABCC3 AK2 ARHGEF16 BCAT1 C1QA CAV2 CCT2 CDK1 CKMT1A CRLS1 CYBA DLC1 ABCC4 AK3 ARID1A BCCIP C1S CBL CCT3 CDK16 CKMT2 CRP CYBB DLGAP5 ABCC5 AKAP1 ARID1B BCL10 C3 CBLC CCT4 CDK2 CKS1B CRTAC1 CYCS DLK1 ABCC6 AKR1B1 ARID2 BCL2 C3AR1 CBX3 CCT5 CDK4 CKS2 CRTC2 CYLD DLL1 ABCD1 AKR1C3 ARMC1 BCL2A1 C5 CBX5 CCT6A CDK5 CLCA2 CRY1 CYP19A1 DLL3 ABCD3 AKT1 ARNT BCL2L1 C5AR1 CCBL2 CCT6B CDK5R1 CLCF1 CRYAA CYP1A1 DLL4
    [Show full text]