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Pheno-RNA, a method to associate genes with a specific phenotype, identifies genes linked to cellular transformation.

ABSTRACT: Cellular transformation is associated with dramatic changes in gene expression, but it is difficult to determine which regulated genes are oncogenically relevant. Here we describe Pheno-RNA, a general approach to identifying candidate genes associated with a specific phenotype. Specifically, we generate a "phenotypic series" by treating a nontransformed breast cell line with a wide variety of molecules that induce cellular transformation to various extents. By performing transcriptional profiling across this phenotypic series, the expression profile of every gene can be correlated with the strength of the transformed phenotype. We identify ∼200 genes whose expression profiles are very highly correlated with the transformation phenotype, strongly suggesting their importance in transformation. Within biological categories linked to cancer, some genes show high correlations with the transformed phenotype, but others do not. Many genes whose expression profiles are highly correlated with transformation have never been associated with cancer, suggesting the involvement of heretofore unknown genes in cancer.

SUBMITTER: Darwiche R

PROVIDER: S-EPMC7682411 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Pheno-RNA, a method to associate genes with a specific phenotype, identifies genes linked to cellular transformation.

Darwiche Rabih R Struhl Kevin K

Proceedings of the National Academy of Sciences of the United States of America 20201103 46

Cellular transformation is associated with dramatic changes in gene expression, but it is difficult to determine which regulated genes are oncogenically relevant. Here we describe Pheno-RNA, a general approach to identifying candidate genes associated with a specific phenotype. Specifically, we generate a "phenotypic series" by treating a nontransformed breast cell line with a wide variety of molecules that induce cellular transformation to various extents. By performing transcriptional profilin ...[more]

PMID: 33144504

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Project description:Thoracic aortic aneurysms result from dysregulated remodeling of the vascular extracellular matrix, which may occur as a result of altered resident cellular function. The present study tested the hypothesis that aortic fibroblasts undergo a stable change in cellular phenotype during thoracic aortic aneurysm formation.Primary murine aortic fibroblasts were isolated from normal and thoracic aortic aneurysm-induced aortas (4 weeks post induction with 0.5 mol/L CaCl(2) 15 minutes) by the outgrowth method. Normal and thoracic aortic aneurysm cultures were examined using a focused polymerase chain reaction array to determine fibroblast-specific changes in gene expression in the absence and presence of biological stimulation (endothelin-1, phorbol-12-myristate-13-acetate, angiotensin-II). The relative expression of 38 genes, normalized to 4 housekeeping genes, was determined, and genes displaying a minimum 2-fold increase/decrease or genes with significantly different normalized cycle threshold values were considered to have altered expression.At steady state, thoracic aortic aneurysm fibroblasts revealed elevated expression of several matrix metalloproteinases (Mmp2, Mmp11, Mmp14), collagen genes/elastin (Col1a1, Col1a2, Col3a1, Eln), and other matrix proteins, as well as decreased expression of Mmp3, Timp3, and Ltbp1. Moreover, gene expression profiles in thoracic aortic aneurysm fibroblasts were different than normal fibroblasts after equivalent biological stimuli.This study demonstrated for the first time that isolated primary aortic fibroblasts from thoracic aortic aneurysm-induced mice possess a unique and stable gene expression profile, and when challenged with biological stimuli, induce a transcriptional response that is different from normal aortic fibroblasts. Together, these data suggest that aortic fibroblasts undergo a stable phenotypic change during thoracic aortic aneurysm development, which may drive the enhancement of extracellular matrix proteolysis in thoracic aortic aneurysm progression.

Dataset Information

Pheno-RNA, a method to associate genes with a specific phenotype, identifies genes linked to cellular transformation.

Publications

Pheno-RNA, a method to associate genes with a specific phenotype, identifies genes linked to cellular transformation.

Similar Datasets

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