Molecular Signature of CAID Syndrome: Noncanonical Roles of SGO1 in Regulation of TGF-β Signaling and EpigenomicsSummary
| Autor: | Jessica Piché, Natacha Gosset, Lisa-Marie Legault, Alain Pacis, Andrea Oneglia, Maxime Caron, Philippe Chetaille, Luis Barreiro, Donghai Liu, Xioyan Qi, Stanley Nattel, Séverine Leclerc, Mélanie Breton-Larrivée, Serge McGraw, Gregor Andelfinger, Jeroen Bakkers, Bart Loeys, Michel Pucéat |
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| Přispěvatelé: | Hubrecht Institute for Developmental Biology and Stem Cell Research, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), CoHEART Consortium |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Epigenomics Potassium Channels IK1 inward rectifying potassium current Proteome SILAC stable isotope labeling by amino acids in cell culture Bisulfite sequencing Medizin Cell Cycle Proteins ERK extracellular signal–regulated kinase Transcriptome 0302 clinical medicine PCR polymerase chain reaction Transforming Growth Factor beta p passage number Original Research TGF-β Signaling TPM tropomyosin Gastroenterology Dermis Syndrome Phenotype CAID chronic atrial and intestinal dysrhythmia mRNA messenger RNA 3. Good health Chromatin Cell biology DNA methylation DAB 3 3′-diaminobenzidine tetra hydrochloride 030211 gastroenterology & hepatology Epigenetics RMP resting membrane potential Signal Transduction Adult FDR false discovery rate JNK c-Jun-N-terminal kinase RRBS reduced representative bisulfite sequencing Biology TGF-beta Signaling 03 medical and health sciences TGF-β transforming growth factor-β Cardiac conduction Chronic Intestinal Pseudo-obstruction GO Gene Ontology Humans Abnormalities Multiple CIPO chronic intestinal pseudo-obstruction lcsh:RC799-869 [SDV.GEN]Life Sciences [q-bio]/Genetics Hepatology Gene Expression Profiling Reproducibility of Results DNA Methylation Fibroblasts CAID Syndrome (Chronic Atrial and Intestinal Dysrhythmia) TAGLN Transgelin ATAC assay for transposase-accessible chromatin with high throughput 030104 developmental biology Gene Ontology lcsh:Diseases of the digestive system. Gastroenterology Human medicine MAPK mitogen-activated protein kinase |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology, Vol 7, Iss 2, Pp 411-431 (2019) Cellular and Molecular Gastroenterology and Hepatology CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY, 7(2), 411-431 CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY, 2019, 7 (2), pp.411-431. ⟨10.1016/j.jcmgh.2018.10.011⟩ CMGH Cellular and Molecular Gastroenterology and Hepatology |
| ISSN: | 2352-345X |
| DOI: | 10.1016/j.jcmgh.2018.10.011⟩ |
| Popis: | Background & Aims A generalized human pacemaking syndrome, chronic atrial and intestinal dysrhythmia (CAID) (OMIM 616201), is caused by a homozygous SGO1 mutation (K23E), leading to chronic intestinal pseudo-obstruction and arrhythmias. Because CAID patients do not show phenotypes consistent with perturbation of known roles of SGO1, we hypothesized that noncanonical roles of SGO1 drive the clinical manifestations observed. Methods To identify a molecular signature for CAID syndrome, we achieved unbiased screens in cell lines and gut tissues from CAID patients vs wild-type controls. We performed RNA sequencing along with stable isotope labeling with amino acids in cell culture. In addition, we determined the genome-wide DNA methylation and chromatin accessibility signatures using reduced representative bisulfite sequencing and assay for transposase-accessible chromatin with high-throughput sequencing. Functional studies included patch-clamp, quantitation of transforming growth factor-β (TGF-β) signaling, and immunohistochemistry in CAID patient gut biopsy specimens. Results Proteome and transcriptome studies converge on cell-cycle regulation, cardiac conduction, and smooth muscle regulation as drivers of CAID syndrome. Specifically, the inward rectifier current, an important regulator of cellular function, was disrupted. Immunohistochemistry confirmed overexpression of Budding Uninhibited By Benzimidazoles 1 (BUB1) in patients, implicating the TGF-β pathway in CAID pathogenesis. Canonical TGF-β signaling was up-regulated and uncoupled from noncanonical signaling in CAID patients. Reduced representative bisulfite sequencing and assay for transposase-accessible chromatin with high-throughput sequencing experiments showed significant changes of chromatin states in CAID, pointing to epigenetic regulation as a possible pathologic mechanism. Conclusions Our findings point to impaired inward rectifier potassium current, dysregulation of canonical TGF-β signaling, and epigenetic regulation as potential drivers of intestinal and cardiac manifestations of CAID syndrome. Transcript profiling and genomics data are as follows: repository URL: https://www.ncbi.nlm.nih.gov/geo; SuperSeries GSE110612 was composed of the following subseries: GSE110309, GSE110576, and GSE110601. Graphical abstract |
| Databáze: | OpenAIRE |
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