A tissue-specific gene expression template portrays heart development and pathology
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A tissue-specific gene expression template portrays heart development and pathology Amy Rodemoyer1, Nataliya Kibiryeva2,3, Alexis Bair2,3, Jennifer Marshall2,3, James E O’Brien Jr2,3 and Douglas C Bittel2,3*
Abstract Congenital heart defects (CHD) are the most common cause of death in children under the age of 1. Tetralogy of Fallot (TOF) is a severe CHD that results from developmental defects in the conotruncal outflow tract. Recently, a tissue-specific gene expression template (GET) was derived from microarray data that accurately characterized multiple normal human tissues. We used the GET to examine spatial, temporal, and a pathological condition (TOF) within a single organ, the heart. The GET, as previously defined, generally identified temporal and spatial differences in the cardiac tissue. Differences in the stoichiometry of the GET reflected the severe developmental disturbance associated with TOF. Our analysis suggests that the homoeostatic equilibrium assessed by the GET at the inter-organ level is generally maintained at the intra-organ level as well. Keywords: Gene expression template, Congenital heart defect, Tetralogy of Fallot
Background With the advent of tools for whole transcriptome analysis, there has been great interest in defining the gene expression profile of normal tissues as well as pathological states in order to understand the genetic regulation of development and identify potential therapeutic targets [1-5]. These studies have produced insight into the complexity of temporal and spatial regulation of gene expression. They also illustrate the interconnected nature of genes, forming pathways that are themselves interconnected. Congenital heart defects (CHD) are the most common birth defect and are the highest cause of mortality in children under the age of 1. Tetralogy of Fallot (TOF) is a severe constellation of defects that results from a disruption of the communication pathways between the first and second heart fields at about 20 days of gestation. A multitude of genes and genetic networks contribute to the spatial and temporal specification required for proper embryological heart formation [6-11]. Variation in the expression of cardiac genes or genes involved in network buffering, variation in the expression of microRNAs, and/or methylation * Correspondence: [email protected] 2 The Ward Family Heart Center, Children's Mercy Hospitals and Clinics, Kansas City, MO 64108, USA 3 University of Missouri-Kansas City School of Medicine, 5100 Rockhill Rd, Kansas City, MO 64110, USA Full list of author information is available at the end of the article
differences or differences in gene transcript processing, could all cause shifts in pathway function leading to failure of the tight control of cell lineage specification required for normal heart development. However, even with the sophisticated tools that allow whole genome analysis, we still know relatively little about the genetic causes of TOF, as is the case for most CHDs. The complexity of the cardiac regula
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