DNA Microarray Reveals Novel Genes Induced by Mechanical Forces in Fetal Lung Type II Epithelial Cells

Department of Pediatrics, Brown University, Providence, Rhode Island, United States
Pediatric Research (Impact Factor: 2.31). 09/2006; 60(2):118-24. DOI: 10.1203/01.pdr.0000227479.73003.b5
Source: PubMed


Mechanical forces are essential for normal fetal lung development. However, the cellular and molecular mechanisms regulating this process are still poorly defined. In this study, we used oligonucleotide microarrays to investigate gene expression in cultured embryonic d 19 rat fetal lung type II epithelial cells exposed to a level of mechanical strain similar to the developing lung. Significance Analysis of Microarrays (SAM) identified 92 genes differentially expressed by strain. Interestingly, several members of the solute carrier family of amino acid transporter (Slc7a1, Slc7a3, Slc6a9, and tumor-associated protein 1) genes involved in amino acid synthesis (Phgdh, Psat1, Psph, Cars, and Asns), as well as the amiloride-sensitive epithelial sodium channel gene (Scnn1a) were up-regulated by the application of force. These results were confirmed by quantitative real-time PCR (qRT-PCR). Thus, this study identifies genes induced by strain that may be important for amino acid signaling pathways and protein synthesis in fetal type II cells. In addition, these data suggest that mechanical forces may contribute to facilitate lung fluid reabsorption in preparation for birth. Taken together, the present investigation provides further insights into how mechanical forces may modulate fetal lung development.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Fetal lung growth and functional differentiation are affected strongly by the extent that pulmonary tissue is distended (expanded) by liquid that naturally fills developing future airspaces. Methods that prevent normal egress of this lung fluid through the trachea magnify mechanical stretching of lung parenchymal cells, thereby promoting lung development. Indeed, experimental observations demonstrate that in utero tracheal occlusion (TO) performed on fetuses during the late canalicular-early saccular stage potently stimulates pulmonary growth and maturation. In this review, we present the four principle non-human animal models of TO/obstruction and discuss them in relation to their utility in elucidating lung development, in remedying congenital diaphragmatic hernia (CDH) as well as in investigating the stretching effects on growth and remodeling of the fine vasculature.
    No preview · Article · May 2007 · American Journal of Medical Genetics Part C Seminars in Medical Genetics
  • [Show abstract] [Hide abstract]
    ABSTRACT: The widespread use of microarray technology and sequencing of genomes has made it increasingly possible to study the cellular sub-systems of organisms. Computational techniques applied to sequence data annotated with ontologies such as the gene ontology (GO) aid in understanding regulatory networks of genes. An important related problem is the estimation of the similarity between gene products based on their annotations. We present an approach to compute gene product similarity that takes into account both the hierarchical nature of GO and the co-occurrence of GO terms in annotations. It also accounts for differences in the cardinality of annotations and differences in the frequency of usage of GO terms. We demonstrate the validity of the metric by computing the similarity between gene products in several different contexts. These include the analysis of similarity within a specific signaling pathway, between proteins constituting a sequence family and the comparative evaluation of different clusterings of microarray data.
    No preview · Conference Paper · Dec 2007
  • [Show abstract] [Hide abstract]
    ABSTRACT: Although transcriptional control is key for proper lung development, little is known about the possible accompanying epigenetic modifications. Here, we have used gene expression profiling to identify 99 genes that are upregulated in fetal lung and 354 genes that are upregulated in adult lung. From the differentially expressed genes, we analyzed the accompanying 5'-UTR methylation profiles of 43 genes. Out of these, nine genes (COL11A1, MEOX2, SERPINE2, SOX9, FBN2, MDK, COL1A1, LAPTM5 and MARCO) displayed an inverse correlation of their 5'-UTR methylation and the cognate gene expression, suggesting that these genes are at least partially regulated by DNA methylation. Using the differential gene expression/DNA methylation profiles as a guidepost, we identified four genes (MEOX2, MDK, LAPTM5, FGFR3) aberrantly methylated in lung cancer. MEOX2 was uniformly higher methylated in all lung cancer samples (n=15), while the methylation of the other three genes was correlated with either the differentiation state of the tumor (MDK, LAPTM5) or the tumor type itself (FGFR3).
    No preview · Article · Feb 2008 · The International Journal of Biochemistry & Cell Biology
Show more