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Plos Genetics : Disease-related Growth Factor and Embryonic Signaling Pathways Modulate an Enhancer of Tcf21 Expression at the 6Q23.2 Coronary Heart Disease Locus, Volume 9

By Gibson, Greg

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Book Id: WPLBN0003952877
Format Type: PDF eBook :
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Reproduction Date: 2015

Title: Plos Genetics : Disease-related Growth Factor and Embryonic Signaling Pathways Modulate an Enhancer of Tcf21 Expression at the 6Q23.2 Coronary Heart Disease Locus, Volume 9  
Author: Gibson, Greg
Volume: Volume 9
Language: English
Subject: Journals, Science, Genetics
Collections: Periodicals: Journal and Magazine Collection (Contemporary), PLoS Genetics
Historic
Publication Date:
Publisher: Plos

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Gibson, G. (n.d.). Plos Genetics : Disease-related Growth Factor and Embryonic Signaling Pathways Modulate an Enhancer of Tcf21 Expression at the 6Q23.2 Coronary Heart Disease Locus, Volume 9. Retrieved from http://worldlibrary.in/


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Description : Coronary heart disease (CHD) is the leading cause of mortality in both developed and developing countries worldwide. Genome-wide association studies (GWAS) have now identified 46 independent susceptibility loci for CHD, however, the biological and disease-relevant mechanisms for these associations remain elusive. The large-scale meta-analysis of GWAS recently identified in Caucasians a CHD-associated locus at chromosome 6q23.2, a region containing the transcription factor TCF21 gene. TCF21 (Capsulin/Pod1/Epicardin) is a member of the basic-helix-loop-helix (bHLH) transcription factor family, and regulates cell fate decisions and differentiation in the developing coronary vasculature. Herein, we characterize a cisregulatory mechanism by which the lead polymorphism rs12190287 disrupts an atypical activator protein 1 (AP-1) element, as demonstrated by allele-specific transcriptional regulation, transcription factor binding, and chromatin organization, leading to altered TCF21 expression. Further, this element is shown to mediate signaling through platelet-derived growth factor receptor beta (PDGFR-b) and Wilms tumor 1 (WT1) pathways. A second disease allele identified in East Asians also appears to disrupt an AP-1-like element. Thus, both disease-related growth factor and embryonic signaling pathways may regulate CHD risk through two independent alleles at TCF21.

 

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