DACH1 protects podocytes from experimental diabetic injury and modulates PTIP-H3K4Me3 activity
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.
| Errataetall: |
CommentIn: J Clin Invest. 2021 May 17;131(10):. - PMID 33998596 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:131 |
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| Enthalten in: |
The Journal of clinical investigation - 131(2021), 10 vom: 17. Mai |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Cao, Aili [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 05.10.2021 Date Revised 05.10.2021 published: Print CommentIn: J Clin Invest. 2021 May 17;131(10):. - PMID 33998596 Citation Status MEDLINE |
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| doi: |
10.1172/JCI141279 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM325498822 |
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| 100 | 1 | |a Cao, Aili |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a DACH1 protects podocytes from experimental diabetic injury and modulates PTIP-H3K4Me3 activity |
| 264 | 1 | |c 2021 | |
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| 500 | |a Date Completed 05.10.2021 | ||
| 500 | |a Date Revised 05.10.2021 | ||
| 500 | |a published: Print | ||
| 500 | |a CommentIn: J Clin Invest. 2021 May 17;131(10):. - PMID 33998596 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Chronic kidney disease | |
| 650 | 4 | |a Diabetes | |
| 650 | 4 | |a Epigenetics | |
| 650 | 4 | |a Nephrology | |
| 650 | 7 | |a DNA-Binding Proteins |2 NLM | |
| 650 | 7 | |a Dach1 protein, mouse |2 NLM | |
| 650 | 7 | |a Eye Proteins |2 NLM | |
| 650 | 7 | |a Histones |2 NLM | |
| 650 | 7 | |a Paxip1 protein, mouse |2 NLM | |
| 650 | 7 | |a histone H3 trimethyl Lys4 |2 NLM | |
| 700 | 1 | |a Li, Jianhua |e verfasserin |4 aut | |
| 700 | 1 | |a Asadi, Morad |e verfasserin |4 aut | |
| 700 | 1 | |a Basgen, John M |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Bingbing |e verfasserin |4 aut | |
| 700 | 1 | |a Yi, Zhengzi |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Song |e verfasserin |4 aut | |
| 700 | 1 | |a Doke, Tomohito |e verfasserin |4 aut | |
| 700 | 1 | |a El Shamy, Osama |e verfasserin |4 aut | |
| 700 | 1 | |a Patel, Niralee |e verfasserin |4 aut | |
| 700 | 1 | |a Cravedi, Paolo |e verfasserin |4 aut | |
| 700 | 1 | |a Azeloglu, Evren U |e verfasserin |4 aut | |
| 700 | 1 | |a Campbell, Kirk N |e verfasserin |4 aut | |
| 700 | 1 | |a Menon, Madhav |e verfasserin |4 aut | |
| 700 | 1 | |a Coca, Steve |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Weijia |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Hao |e verfasserin |4 aut | |
| 700 | 1 | |a Zen, Ke |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Zhihong |e verfasserin |4 aut | |
| 700 | 1 | |a Murphy, Barbara |e verfasserin |4 aut | |
| 700 | 1 | |a He, John C |e verfasserin |4 aut | |
| 700 | 1 | |a D'Agati, Vivette D |e verfasserin |4 aut | |
| 700 | 1 | |a Susztak, Katalin |e verfasserin |4 aut | |
| 700 | 1 | |a Kaufman, Lewis |e verfasserin |4 aut | |
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