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Cistrome of the aldosterone-activated mineralocorticoid receptor in human renal cells. | LitMetric

Cistrome of the aldosterone-activated mineralocorticoid receptor in human renal cells.

FASEB J

*Unité 1185, Institut National de la Santé et de la Recherche Médicale, Le Kremlin-Bicêtre, France; Faculté de Médecine Paris-Sud, Unité Mixte de Recherche-S1185, Université Paris-Sud, Le Kremlin-Bicêtre, France; and Service de Génétique Moléculaire, Pharmacogénétique et d'Hormonologie and Service d'Endocrinologie et des Maladies de la Reproduction, Hôpital de Bicêtre, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, France

Published: September 2015

AI Article Synopsis

Article Abstract

Aldosterone exerts its effects mainly by activating the mineralocorticoid receptor (MR), a transcription factor that regulates gene expression through complex and dynamic interactions with coregulators and transcriptional machinery, leading to fine-tuned control of vectorial ionic transport in the distal nephron. To identify genome-wide aldosterone-regulated MR targets in human renal cells, we set up a chromatin immunoprecipitation (ChIP) assay by using a specific anti-MR antibody in a differentiated human renal cell line expressing green fluorescent protein (GFP)-MR. This approach, coupled with high-throughput sequencing, allowed identification of 974 genomic MR targets. Computational analysis identified an MR response element (MRE) including single or multiple half-sites and palindromic motifs in which the AGtACAgxatGTtCt sequence was the most prevalent motif. Most genomic MR-binding sites (MBSs) are located >10 kb from the transcriptional start sites of target genes (84%). Specific aldosterone-induced recruitment of MR on the first most relevant genomic sequences was further validated by ChIP-quantitative (q)PCR and correlated with concomitant and positive aldosterone-activated transcriptional regulation of the corresponding gene, as assayed by RT-qPCR. It was notable that most MBSs lacked MREs but harbored DNA recognition motifs for other transcription factors (FOX, EGR1, AP1, PAX5) suggesting functional interaction. This work provides new insights into aldosterone MR-mediated renal signaling and opens relevant perspectives for mineralocorticoid-related pathophysiology.

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Source
http://dx.doi.org/10.1096/fj.15-274266DOI Listing

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