A single genetic locus controls both expression of DPEP1/CHMP1A and kidney disease development via ferroptosis

Genome-wide association studies (GWAS) have identified loci for kidney disease, but the causal variants, genes, and pathways remain unknown. Here we identify two kidney disease genes Dipeptidase 1 (DPEP1) and Charged Multivesicular Body Protein 1 A (CHMP1A) via the triangulation of kidney function G...

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Autores principales: Guan, Yuting, Liang, Xiujie, Ma, Ziyuan, Hu, Hailong, Liu, Hongbo, Miao, Zhen, Linkermann, Andreas, Hellwege, Jacklyn N., Voight, Benjamin F., Susztak, Katalin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382756/
https://www.ncbi.nlm.nih.gov/pubmed/34426578
http://dx.doi.org/10.1038/s41467-021-25377-x
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author Guan, Yuting
Liang, Xiujie
Ma, Ziyuan
Hu, Hailong
Liu, Hongbo
Miao, Zhen
Linkermann, Andreas
Hellwege, Jacklyn N.
Voight, Benjamin F.
Susztak, Katalin
author_facet Guan, Yuting
Liang, Xiujie
Ma, Ziyuan
Hu, Hailong
Liu, Hongbo
Miao, Zhen
Linkermann, Andreas
Hellwege, Jacklyn N.
Voight, Benjamin F.
Susztak, Katalin
author_sort Guan, Yuting
collection PubMed
description Genome-wide association studies (GWAS) have identified loci for kidney disease, but the causal variants, genes, and pathways remain unknown. Here we identify two kidney disease genes Dipeptidase 1 (DPEP1) and Charged Multivesicular Body Protein 1 A (CHMP1A) via the triangulation of kidney function GWAS, human kidney expression, and methylation quantitative trait loci. Using single-cell chromatin accessibility and genome editing, we fine map the region that controls the expression of both genes. Mouse genetic models demonstrate the causal roles of both genes in kidney disease. Cellular studies indicate that both Dpep1 and Chmp1a are important regulators of a single pathway, ferroptosis and lead to kidney disease development via altering cellular iron trafficking.
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spelling pubmed-83827562021-09-22 A single genetic locus controls both expression of DPEP1/CHMP1A and kidney disease development via ferroptosis Guan, Yuting Liang, Xiujie Ma, Ziyuan Hu, Hailong Liu, Hongbo Miao, Zhen Linkermann, Andreas Hellwege, Jacklyn N. Voight, Benjamin F. Susztak, Katalin Nat Commun Article Genome-wide association studies (GWAS) have identified loci for kidney disease, but the causal variants, genes, and pathways remain unknown. Here we identify two kidney disease genes Dipeptidase 1 (DPEP1) and Charged Multivesicular Body Protein 1 A (CHMP1A) via the triangulation of kidney function GWAS, human kidney expression, and methylation quantitative trait loci. Using single-cell chromatin accessibility and genome editing, we fine map the region that controls the expression of both genes. Mouse genetic models demonstrate the causal roles of both genes in kidney disease. Cellular studies indicate that both Dpep1 and Chmp1a are important regulators of a single pathway, ferroptosis and lead to kidney disease development via altering cellular iron trafficking. Nature Publishing Group UK 2021-08-23 /pmc/articles/PMC8382756/ /pubmed/34426578 http://dx.doi.org/10.1038/s41467-021-25377-x Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Guan, Yuting
Liang, Xiujie
Ma, Ziyuan
Hu, Hailong
Liu, Hongbo
Miao, Zhen
Linkermann, Andreas
Hellwege, Jacklyn N.
Voight, Benjamin F.
Susztak, Katalin
A single genetic locus controls both expression of DPEP1/CHMP1A and kidney disease development via ferroptosis
title A single genetic locus controls both expression of DPEP1/CHMP1A and kidney disease development via ferroptosis
title_full A single genetic locus controls both expression of DPEP1/CHMP1A and kidney disease development via ferroptosis
title_fullStr A single genetic locus controls both expression of DPEP1/CHMP1A and kidney disease development via ferroptosis
title_full_unstemmed A single genetic locus controls both expression of DPEP1/CHMP1A and kidney disease development via ferroptosis
title_short A single genetic locus controls both expression of DPEP1/CHMP1A and kidney disease development via ferroptosis
title_sort single genetic locus controls both expression of dpep1/chmp1a and kidney disease development via ferroptosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382756/
https://www.ncbi.nlm.nih.gov/pubmed/34426578
http://dx.doi.org/10.1038/s41467-021-25377-x
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