DACH1 protects podocytes from experimental diabetic injury and modulates PTIP-H3K4Me3 activity
Aili Cao, … , Katalin Susztak, Lewis Kaufman
Aili Cao, … , Katalin Susztak, Lewis Kaufman
Published May 17, 2021
Citation Information: J Clin Invest. 2021;131(10):e141279. https://doi.org/10.1172/JCI141279.
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Research Article Nephrology

DACH1 protects podocytes from experimental diabetic injury and modulates PTIP-H3K4Me3 activity

Abstract

Dachshund homolog 1 (DACH1), a key cell-fate determinant, regulates transcription by DNA sequence–specific binding. We identified diminished Dach1 expression in a large-scale screen for mutations that convert injury-resistant podocytes into injury-susceptible podocytes. In diabetic kidney disease (DKD) patients, podocyte DACH1 expression levels are diminished, a condition that strongly correlates with poor clinical outcomes. Global Dach1 KO mice manifest renal hypoplasia and die perinatally. Podocyte-specific Dach1 KO mice, however, maintain normal glomerular architecture at baseline, but rapidly exhibit podocyte injury after diabetes onset. Furthermore, podocyte-specific augmentation of DACH1 expression in mice protects from DKD. Combined RNA sequencing and in silico promoter analysis reveal conversely overlapping glomerular transcriptomic signatures between podocyte-specific Dach1 and Pax transactivation-domain interacting protein (Ptip) KO mice, with upregulated genes possessing higher-than-expected numbers of promoter Dach1-binding sites. PTIP, an essential component of the activating histone H3 lysine 4 trimethylation (H3K4Me3) complex, interacts with DACH1 and is recruited by DACH1 to its promoter-binding sites. DACH1-PTIP recruitment represses transcription and reduces promoter H3K4Me3 levels. DACH1 knockdown in podocytes combined with hyperglycemia triggers target gene upregulation and increases promoter H3K4Me3. These findings reveal that in DKD, diminished DACH1 expression enhances podocyte injury vulnerability via epigenetic derepression of its target genes.

Authors

Aili Cao, Jianhua Li, Morad Asadi, John M. Basgen, Bingbing Zhu, Zhengzi Yi, Song Jiang, Tomohito Doke, Osama El Shamy, Niralee Patel, Paolo Cravedi, Evren U. Azeloglu, Kirk N. Campbell, Madhav Menon, Steve Coca, Weijia Zhang, Hao Wang, Ke Zen, Zhihong Liu, Barbara Murphy, John C. He, Vivette D. D’Agati, Katalin Susztak, Lewis Kaufman

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Figure 10

Proposed mechanism of transcriptional derepression of DACH1 target genes in human DKD.

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Proposed mechanism of transcriptional derepression of DACH1 target genes...
Previous studies show that PTIP is recruited by Pax proteins to promoter Pax response elements (PREs) and that this enhances promoter H3K4Me3 levels and causes transcriptional activation (24). In the current work, we show that PTIP can also be recruited by sequence-specific binding of DACH1 to its target gene promoters, but that this recruitment suppresses transcription and reduces promoter H3K4Me3 levels. We propose that in DKD, reduced levels of podocyte DACH1 expression cause diminished recruitment of PTIP by DACH1 to its target gene promoters. This, in combination with hyperglycemia, results in increased promoter H3K4Me3 levels and transcriptional derepression of multiple DACH1 target genes.