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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 Article has an altmetric score of 11

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

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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 7

PTIP is recruited by DACH1 to DACH1 DNA binding sites and causes transcriptional repression and decreased H3K4Me3 levels.

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PTIP is recruited by DACH1 to DACH1 DNA binding sites and causes transcr...
(A) Co-IP was performed between PTIP-FLAG and DACH1-V5 using antibodies to their tags. FLAG-RAVER was used as a negative control protein. Indicated lysates were combined and incubated overnight with anti-FLAG antibodies bound to superparamagnetic iron–impregnated beads. A robust protein complex is present between PTIP-FLAG and DACH1-V5, but completely absent between FLAG-RAVER and DACH1-V5. Molecular weight of indicated proteins is as follows: FLAG-RAVER, 95 kDa; DACH1-V5, 105 kDa; PTIP-FLAG, 120 kDa. Protein interaction is robust despite comparatively low expression of PTIP-FLAG. Band indicated by arrow. (B) Schematic of SV40-luciferase reporter plasmids (upper) and DACH1 expression plasmids (lower). DREs were synthesized as a sextet multimer and subcloned immediately upstream of the SV40 promoter. Location of primers used for ChIP-qPCR are indicated. The DACH1 ΔDBD expression plasmid carries a deletion of its box-N domain, which mediates direct binding of DACH1 to DNA. (C) Each of the reporter plasmids was cotransfected with a DACH1 expression plasmid into 293T cells and then luciferase expression measured. Dramatic transcriptional repression was induced by the combined presence of upstream DACH1 DNA binding sites and a DACH1 protein able to bind to these sites. *P < 0.0001. (D) ChIP-qPCR was performed using an antibody specific for PTIP and primer pairs indicated in B. *P < 0.0001; **P < 0.0001. (E) ChIP-qPCR as in D, but with an H3K4Me3 antibody. *P < 0.0001; **P < 0.0001. (C–E) One-way ANOVA and Tukey’s post hoc test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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