Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10143483 | Gene | 2018 | 39 Pages |
Abstract
In mammalian cells TPP1, encoded by the Acd gene, is a key component of the shelterin complex, which is required for telomere length maintenance and telomere protection. In mice, a hypomorphic mutation in Acd causes the adrenocortical dysplasia (acd) phenotype, which includes limb and body axis anomalies, and perinatal lethality. p53 deficiency partially rescues limb and body axis anomalies in acd mutant embryos, but not perinatal lethality, implicating p53-independent mechanisms in the acd phenotype. Loss of function of most shelterin proteins results in early embryonic lethality. Thus, study of the hypomorphic acd allele provides a unique opportunity to understand telomere dysfunction at an organismal level. The aim of this study was to identify transcriptome alterations in acd mutant and acd, p53 double mutant embryos to understand the p53-dependent and -independent factors that contribute to the mutant phenotypes in the context of the whole organism. Genes involved in developmental processes, cell cycle, metabolic pathways, tight junctions, axon guidance and signaling pathways were regulated by p53-driven mechanisms in acd mutant embryos, while genes functioning in immune response, and RNA processing were altered independently of p53 in acd, p53 double mutant embryos. To our best of knowledge, this is the first study revealing detailed transcriptomic alterations, reflecting novel p53-dependent and -independent pathways contributing to the acd phenotype. Our data confirm the importance of cell cycle and DNA repair pathways, and suggest novel links between telomere dysfunction and immune system regulation and the splicing machinery. Given the broad applicability of telomere maintenance in growth, development, and genome stability, our data will also provide a rich resource for others studying telomere maintenance and DNA damage responses in mammalian model systems.
Keywords
ECMCelp53qPCRmRNADDRMEFmTORGEOUCSCRT-qPCRCRSCCl4CXCL14ACDWntCXCL12C57BL6/jCyclin D1HHSHoyeraal-Hreidarsson syndromeVACTERLFgf10IFIT1CASP3TPP1BARD1USP18JAK-STATCCND1TIN2POT1FGF4wingless-type MMTV integration site familyJAK1Janus kinase 1RAP1IGFBP3XIAPCCL25ERBBCDKN1AGadd45bCAST/EiFGF13μgMicrogramTRF2TRF1RAD21TERCIrgm1CCL8DDB2RLECyclin G1FGF3Trp53GnRHchemokine (C-X-C motif) ligand 12ubiquitin specific peptidase 18chemokine (C-C motif) ligand 4Telomerase RNA componentUTRKEGGcDNAComplementary DNADNAMAPKmessenger RNAdeoxyribonucleic acidRNAribonucleic acidGene expressionTERTPathway analysisANOVAone-way analysis of varianceTelomerase reverse transcriptasebase pairUniversity of California, Santa CruzKyoto Encyclopedia of Genes and GenomesDeltaDAVIDquantitative reverse transcription PCRMicroarrayRINCaudal regression syndromeRNA Integrity Numberfibroblast growth factor 10fibroblast growth factor 4Vascular endothelial growth factorVascular Endothelial Growth Factor (VEGF)biological processphosphatase and tensin homologExtracellular matrixuntranslated regionX-linked inhibitor of apoptosismouse embryonic fibroblastswild typeGene ontologyGonadotropin-releasing hormoneDNA damage responsequantitative polymerase chain reactionthe Database for Annotation, Visualization and Integrated DiscoveryInsulin-like growth factor binding protein 3mitogen-activated protein kinasePtenGene Expression Omnibusjanus kinase/signal transducers and activators of transcriptioncaspase 3Dyskeratosis congenita
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Authors
Ceren Sucularli, Peedikayil Thomas, Hande Kocak, James S. White, Bridget C. O'Connor, Catherine E. Keegan,