Feedback regulation by Atf3 in the endothelin-1-responsive transcriptome of cardiomyocytes: Egr1 is a principal Atf3 target

Giraldo, A., Barrett, O. P. T., Tindall, M. J., Fuller, S. J., Amirak, E., Bhattacharya, B. S., Sugden, P. H. and Clerk, A. ORCID: https://orcid.org/0000-0002-5658-0708 (2012) Feedback regulation by Atf3 in the endothelin-1-responsive transcriptome of cardiomyocytes: Egr1 is a principal Atf3 target. Biochemical Journal, 444 (2). pp. 343-355. ISSN 0264-6021 doi: 10.1042/BJ20120125

Abstract/Summary

Endothelin-1 promotes cardiomyocyte hypertrophy by inducing changes in gene expression. Immediate early genes including activating transcription factor 3 (Atf3), Egr1 and Ptgs2 are rapidly and transiently upregulated by endothelin-1 in cardiomyocytes. Atf3 regulates expression of downstream genes and is implicated in negative feedback regulation of other immediate early genes. To identify Atf3-regulated genes, we knocked down Atf3 expression in cardiomyocytes exposed to endothelin-1 and used microarrays to interrogate the transcriptomic effects. Of upregulated mRNAs, expression of 23 (including Egr1, Ptgs2) was enhanced and expression of 25 was inhibited by Atf3 knockdown. Using quantitative PCR, we determined that knockdown of Atf3 had little effect on upregulation of Egr1 mRNA over 30 min, but abolished the subsequent decline, causing sustained Egr1 mRNA expression and enhanced protein expression. This resulted from direct binding of Atf3 to the Egr1 promoter. Mathematical modelling established that Atf3 can suffice to suppress Egr1 expression. Given the widespread co-regulation of Atf3 with Egr1, we suggest that the Atf3-Egr1 negative feedback loop is of general significance. Loss of Atf3 caused abnormal cardiomyocyte growth, presumably resulting from dysregulation of target genes. Our data therefore identify Atf3 as a nexus in cardiomyocyte hypertrophy required to facilitate the full and proper growth response.

Item Type	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/27916
Identification Number/DOI	10.1042/BJ20120125
Refereed	Yes
Divisions	Interdisciplinary centres and themes > Institute for Cardiovascular and Metabolic Research (ICMR) Life Sciences > School of Biological Sciences > Biomedical Sciences Science > School of Mathematical, Physical and Computational Sciences > Department of Mathematics and Statistics
Uncontrolled Keywords	activating transcription factor 3 (Atf3), early growth response 1 (Egr1), hypertrophy, immediate early gene, microarray, negative feedback
Publisher	Portland Press Limited
Publisher Statement	The final version of record is available at http://www.biochemj.org/bj/444/bj4440343.htm
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