ArticleThe Journal of biological chemistry2009
AF17 competes with AF9 for binding to Dot1a to up-regulate transcription of epithelial Na+ channel alpha.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 51 citations in OpenAlex.
- Effects of genetic variation in H3K79 methylation regulatory genes on clinical blood pressure and blood pressure response to hydrochlorothiazide.Journal of translational medicine · 2012Trial
- Chromatin structure in totipotent mouse early preimplantation embryos.The Journal of reproduction and development · 2024Review
- Epithelial NaComprehensive Physiology · 2024Review
- The DOT1L-MLLT10 complex regulates male fertility and promotes histone removal during spermiogenesis.Development (Cambridge, England) · 2023Article
- Aldosterone: Renal Action and Physiological Effects.Comprehensive Physiology · 2023Article
- Aldosterone inhibits Dot1l expression in guinea pig cochlea.European journal of medical research · 2023Article
- Aldosterone-Regulated Sodium Transport and Blood Pressure.Frontiers in physiology · 2022Review
- Ferulic acid ameliorates lipopolysaccharide-induced tracheal injury via cGMP/PKGII signaling pathway.Respiratory research · 2021Article
- Loss of Histone H3 K79 Methyltransferase Dot1l Facilitates Kidney Fibrosis by Upregulating Endothelin 1 through Histone Deacetylase 2.Journal of the American Society of Nephrology : JASN · 2020Article
- Structural and functional analysis of the DOT1L-AF10 complex reveals mechanistic insights into MLL-AF10-associated leukemogenesis.Genes & development · 2018Article
- The upstreams and downstreams of H3K79 methylation by DOT1L.Chromosoma · 2016Review
- Serum and Glucocorticoid Regulated Kinase 1 in Sodium Homeostasis.International journal of molecular sciences · 2016Review
- Dot1l deficiency leads to increased intercalated cells and upregulation of V-ATPase B1 in mice.Experimental cell research · 2016Article
- Hypertensive epigenetics: from DNA methylation to microRNAs.Journal of human hypertension · 2015Review
- Epigenetics of epithelial Na(+) channel-dependent sodium uptake and blood pressure regulation.World journal of nephrology · 2015Review
- Regulation of αENaC transcription.Vitamins and hormones · 2015Review
- Mineralocorticoid receptor antagonizes Dot1a-Af9 complex to increase αENaC transcription.American journal of physiology. Renal physiology · 2013Article
- Aldosterone-dependent trans-activation and epigenetic derepression of ENaC: where is the balance?American journal of physiology. Renal physiology · 2013Article
- Article
- Epigenetics and the control of the collecting duct epithelial sodium channel.Seminars in nephrology · 2013Review
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
We previously reported that Dot1a.AF9 complex represses transcription of the epithelial Na(+) channel subunit alpha (alpha-ENaC) gene in mouse inner medullary collecting duct mIMCD3 cells and mouse kidney. Aldosterone relieves this repression by down-regulating the complex through various mechanisms. Whether these mechanisms are sufficient and conserved in human cells or can be applied to other aldosterone-regulated genes remains largely unknown. Here we demonstrate that human embryonic kidney 293T cells express the three ENaC subunits and all of the ENaC transcriptional regulators examined. These cells respond to aldosterone and display benzamil-sensitive Na(+) currents, as measured by whole-cell patch clamping. We also show that AF17 and AF9 competitively bind to the same domain of Dot1a in multiple assays and have antagonistic effects on expression of an alpha-ENaC promoter-luciferase construct. Overexpression of Dot1a or AF9 decreased mRNA expression of the ENaC subunits and their transcriptional regulators and reduced benzamil-sensitive Na(+) currents. AF17 overexpression caused the opposite effects, accompanied by redirection of Dot1a from the nucleus to the cytoplasm and reduction in histone H3 K79 methylation. The nuclear export inhibitor leptomycin B blocked the effect of AF17 overexpression on H3 K79 hypomethylation. RNAi-mediated knockdown of AF17 yielded nuclear enrichment of Dot1a and histone H3 K79 hypermethylation. As with AF9, AF17 displays nuclear and cytoplasmic co-localization with Sgk1. Therefore, AF17 competes with AF9 to bind Dot1a, decreases Dot1a nuclear expression by possibly facilitating its nuclear export, and relieves Dot1a.AF9-mediated repression of alpha-ENaC and other target genes.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.