Expression data from embryonic mouse pleuroperitoneal folds and diaphragms
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE35243 | GEO | 2012/02/10
SECONDARY ACCESSION(S): PRJNA151547
REPOSITORIES: GEO
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Project description:Microarray data from this study represent the first global transcriptional survey of gene expression during early compared to late diaphragm formation. Based on the assumption that Congenital diaphragmatic hernia (CDH) candidate genes will have similar temporal expression trends and will be part of the same biological pathways as those already implicated in CDH, we used known CDH-associated genes as “baits” to filter expression microarray data sets (GSEA and STEM) to identify a list of novel CDH candidate genes. Laser-capture microdissected C57BL/6J mouse embryonic diaphragm tissues were studied at three key time-points during normal development. We studied the primordial diaphragm’s pleuroperitoneal folds at E11.5 and E12.5, and the muscularized mature diaphragm at E16.5 to identify genes and pathways that characterize important stages in diaphragm morphogenesis.
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Project description:Congenital diaphragmatic hernia (CDH) is characterized by incomplete closure of the diaphragm and lung hypoplasia. The pathophysiology of lung defects in CDH is poorly understood. To establish a translational model of human airway epithelium in CDH for pathogenic investigation and therapeutic testing, we developed a robust methodology of epithelial progenitor derivation from tracheal aspirates of newborns. Basal stem cells from CDH patients and preterm and term, non-CDH controls were derived and analyzed by bulk RNA-sequencing, ATAC-sequencing, and air-liquid-interface differentiation. Transcriptomic and epigenetic profiling of CDH and non-CDH basal stem cells reveals a disease-specific, proinflammatory signature independent of severity or hernia size. In addition, CDH basal stem cells exhibit defective epithelial differentiation in vitro that recapitulates epithelial phenotypes found in fetal human CDH lung samples and fetal tracheas of the nitrofen rat model of CDH. Furthermore, steroid treatment normalizes epithelial differentiation phenotypes of human CDH basal stem cells in vitro and in nitrofen rat tracheas in vivo. Our findings have identified an interplay between a proinflammatory signature and BSC differentiation as a potential therapeutic target for airway epithelial defects in CDH.
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Project description:<p>Congenital diaphragmatic hernia (CDH) is a common and severe birth defect characterized by structural defects of the diaphragm and by pulmonary hypoplasia. Congenital diaphragmatic hernia patient may present either as an isolated phenotype or together with other congenital anomalies in a complex phenotype. Despite the clinical significance of CDH, the underlying genetic and developmental pathways are incompletely understood.</p> <p>In order to establish a catalog of human genetic variation for this condition, we performed whole exome sequencing (WES) on 275 carefully phenotyped individuals with CDH in the Pediatric Surgical Research Laboratories at the Massachusetts General Hospital (Boston, MA, USA) and Boston Children's Hospital (Boston, MA, USA). The exome data generated are valuable for comparison of candidate genes derived from WES of other CDH cohorts or affected kindreds, and to provide ideal candidates for further functional studies with the ultimate goal of enhancing our understanding of the heterogeneous and, possibly, oligogenic molecular etiology of CDH.</p> <p>While familial clustering has been reported in rare kindreds, the majority of probands with CDH have no family history of CDH leading to the hypothesis that de novo variants are an important and relatively frequent etiological mechanism. In the second version of the study, we performed WES analysis on 87 trios, to assess the contribution of de novo mutations in the etiology of diaphragmatic and pulmonary defects and to identify previously unknown candidate genes. This dbGaP submission includes WES data on: (a) 20 new probands, (b) 9 probands also reported in the previous version (dbGaP accession no. <a href="./study.cgi?study_id=phs000783.v1.p1">phs000783.v1.p1</a>), (c) 174 unaffected parents, including the parents of 67 previously reported probands. Combined analysis with other available cohorts of congenital diaphragmatic hernia revealed a genome-wide enrichment of likely gene-disrupting de novo variants (i.e., nonsense, frameshift or splice site), and missense de novo variants predicted in silico to be damaging.</p>
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Project description:<p>Congenital Diaphragmatic Hernia (CDH) is a common and life-threatening malformation. The most common phenotype is left-sided posterolateral (Bochdalek-type) hernia accompanied by pulmonary hypoplasia. Due to the high mortality, most of the cases have no family history for CDH. The rare presumed Mendelian instances of CDH have the potential to be extremely informative about the molecular mechanisms generating this phenotype. Three multiplex families were deemed meritorious for study by whole exome sequencing: <ol> <li>Parents who were 1<sup>st</sup> cousins gave birth to 2 children with CDH (one of whom also had cleft lip and palate), both now deceased. A DNA sample was available from one child. We proposed to perform a SNP array to identify regions of homozygosity by descent and intersect these regions with variants detected on exome sequencing. This effort has led to the identification of 3 confirmed variants. We are determining which if any are expressed in the primordial developing diaphragm and are also using bioinformatic approaches to determine which of these candidates interact with known CDH genes.</li> <li>This non-consanguineous couple gave birth to 2 affected boys with an identical and lethal CDH phenotype (consisting of diaphragmatic hernia, epigastric hernia, and facial dysmorphism) and one healthy boy. We predicted X-linked inheritance and findings from X chromosome microsatellite marker analysis are consistent with this. Accordingly, we are focusing on sequence variants mapping to the X chromosome. We have identified a single candidate gene and confirmed that the variant follows an X-linked pattern of inheritance in all family members. Expression studies are underway.</li> <li>These affected males are second cousins. By virtue of their position in the pedigree, we predicted an inheritance pattern consistent with X-linked inheritance. Data from WES and microsatellite marker analysis are currently being integrated.</li> </ol> </p>
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Project description:Gene Mutation and Rescue in Human Congenital Diaphragmatic Hernia (CDH)
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