Journal
RNA
Volume 27, Issue 8, Pages 933-945Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1261/rna.078727.121
Keywords
RNA decay; RNA-binding proteins; gene expression kinetics; transcriptomics; steroid hormone
Categories
Funding
- American Heart Association [20PRE35220016]
- Predoctoral Training Grant in Molecular Biology [NIH-T32-GM008730]
- University of Colorado Anschutz Medical Campus RNA Bioscience Initiative
- Boettcher Foundation Webb-Waring Early Career Investigator Award [AWD-103075]
- National Institutes of Health [DK043140]
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The study identified the involvement of RNA-binding proteins and RNA decay in the kinetics of AngII-induced gene expression, which coordinated an increase in both synthesis and decay. This facilitated the major transcriptomic changes required to prevent aldosterone overproduction.
Angiotensin II (AngII) stimulates adrenocortical cells to produce aldosterone, a master regulator of blood pressure. Despite extensive characterization of the transcriptional and enzymatic control of adrenocortical steroidogenesis, there are still major gaps in the precise regulation of AngII-induced gene expression kinetics. Specifically, we do not know the regulatory contribution of RNA-binding proteins (RBPs) and RNA decay, which can control the timing of stimulus-induced gene expression. To investigate this question, we performed a high-resolution RNA-seq time course of the AngII stimulation response and 4-thiouridine pulse labeling in a steroidogenic human cell line (H295R). We identified twelve temporally distinct gene expression responses that contained mRNA encoding proteins known to be important for various steps of aldosterone production, such as cAMP signaling components and steroidogenic enzymes. AngII response kinetics for many of these mRNAs revealed a coordinated increase in both synthesis and decay. These findings were validated in primary human adrenocortical cells stimulated ex vivo with AngII. Using a candidate screen, we identified a subset of RNA-binding protein and RNA decay factors that activate or repress AngII-stimulated aldosterone production. Among the repressors of aldosterone were BTG2, which promotes deadenylation and global RNA decay. BTG2 was induced in response to AngII stimulation and promoted the repression of mRNAs encoding prosteroidogenic factors indicating the existence of an incoherent feedforward loop controlling aldosterone homeostasis. These data support a model in which coordinated increases in transcription and decay facilitate the major transcriptomic changes required to implement a prosteroidogenic expression program that actively resolves to prevent aldosterone overproduction.
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