Molecular Signature of CAID Syndrome: Noncanonical Roles of SGO1 in Regulation of TGF-β Signaling and EpigenomicsSummary
| العنوان: | Molecular Signature of CAID Syndrome: Noncanonical Roles of SGO1 in Regulation of TGF-β Signaling and EpigenomicsSummary |
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| المؤلفون: | 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 |
| المساهمون: | 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 |
| المصدر: | 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 |
| بيانات النشر: | Elsevier, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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/geoTest; SuperSeries GSE110612 was composed of the following subseries: GSE110309, GSE110576, and GSE110601. Graphical abstract |
| وصف الملف: | |
| اللغة: | English |
| تدمد: | 2352-345X |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c86c6072048d78e405868a6d89bbe835Test http://www.sciencedirect.com/science/article/pii/S2352345X18301577Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....c86c6072048d78e405868a6d89bbe835 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 2352345X |
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