High-throughput gene expression analysis identifies p53-dependent and -independent pathways contributing to the adrenocortical dysplasia (acd) phenotype
| Autor: | Ceren Sucularli, James S. White, Hande Kocak, Bridget C. O’Connor, Peedikayil E. Thomas, Catherine E. Keegan |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
DNA repair Telomere-Binding Proteins Mutant Biology medicine.disease_cause Genomic Instability Shelterin Complex Article Transcriptome Mice 03 medical and health sciences Genetics medicine Animals Abnormalities Multiple Gene Regulatory Networks Telomere-binding protein Mutation Gene Expression Profiling Gene Expression Regulation Developmental General Medicine Shelterin Phenotype Cell biology Telomere 030104 developmental biology Adrenal Cortex Tumor Suppressor Protein p53 Signal Transduction |
| Zdroj: | Gene. 679:219-231 |
| ISSN: | 0378-1119 |
| DOI: | 10.1016/j.gene.2018.09.002 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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