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Cistrome of the Aldosterone-activated Mineralocorticoid Receptor in Human Renal Cells. Cistrome of the Aldosterone-activated Mineralocorticoid Receptor in Human Renal Cells: Cistrome of Human Renal Mineralocorticoid Receptor
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Edité par CCSD ; Federation of American Society of Experimental Biology -
International audience. Aldosterone acts 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 the chromatin immunoprecipitation (ChIP) using a specific anti-MR antibody in a differentiated human renal cell line expressing GFP-MR. This approach coupled with high-throughput sequencing allowed identification of 974 genomic MR targets. Computational analysis identified a 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 (MBS) are located at distance >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-qPCR and correlated with concomitant and positive aldosterone-activated transcriptional regulation of the corresponding gene as assayed by RT-qPCR. Interestingly, most MBS lack MRE but harbor 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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