Regulation of mRNA splicing, processing and stability is increasingly recognized as a critical control point in dynamically altering gene expression during stress or disease. Very little is understood of this process in heart failure. Here, we show that BEX1 is a heart failure-induced gene functioning as an mRNA-associated protein that enhances expression of a subset of cardiac disease-promoting genes. Modeling the increase in BEX1 that occurs in disease, cardiac-specific BEX1 transgenic mice show worse cardiac disease with stress stimulation, whereas Bex1 gene-deleted mice are protected from heart failure-promoting insults. Proteomic and interactive screening assays show that BEX1 is part of a large ribonucleoprotein processing complex involved in regulating proinflammatory mRNA expression in the heart. Specifically, induction of BEX1 augments the stability and expression of AU-rich element containing mRNAs typically found within proinflammatory genes. Thus, BEX1 functions as an mRNA-dependent effector that augments pathology-promoting gene expression during heart failure.
Bibliographical noteFunding Information:
We are grateful to Dr Frank L. Margolis (Professor, Department of Anatomy and Neurobiology, University of Maryland) for providing Bex1 knockout mice. We thank Dr Daniel R. Schoenberg, Director of the Ohio State University Center for RNA Biology, for his advises and for providing LM (tk-tTA) cell lines for analysis of the instability element ARE. This work was supported by grants from the NIH (to J.D.M.) and by a NIH R00HL121284 (to F. A.). J.D.M. was also supported by the Howard Hughes Medical Institute.
© 2017 The Author(s).