EZH2 specifically regulates ISL1 during embryonic urinary tract formation.

Autor: Mingardo E; Institute of Anatomy and Cell Biology, Medical Faculty, University of Bonn, 53115, Bonn, Germany.; Institute of Human Genetics, Medical Faculty, University of Bonn, 53127, Bonn, Germany., Kalanithy JC; Institute of Anatomy and Cell Biology, Medical Faculty, University of Bonn, 53115, Bonn, Germany.; Institute of Human Genetics, Medical Faculty, University of Bonn, 53127, Bonn, Germany., Dworschak G; Institute of Human Genetics, Medical Faculty, University of Bonn, 53127, Bonn, Germany.; Institute of Neuroanatomy, Medical Faculty, University of Bonn, 53115, Bonn, Germany.; Department of Neuropediatrics, University Hospital Bonn, 53127, Bonn, Germany., Ishorst N; Institute of Human Genetics, Medical Faculty, University of Bonn, 53127, Bonn, Germany.; Institute of Neuroanatomy, Medical Faculty, University of Bonn, 53115, Bonn, Germany., Yilmaz Ö; Institute of Neuroanatomy, Medical Faculty, University of Bonn, 53115, Bonn, Germany., Lindenberg T; Institute of Neuroanatomy, Medical Faculty, University of Bonn, 53115, Bonn, Germany., Hollstein R; Institute of Human Genetics, Medical Faculty, University of Bonn, 53127, Bonn, Germany., Felger T; Institute of Human Genetics, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany., Angrand PO; Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, F-59000, France., Reutter H; Institute of Human Genetics, Medical Faculty, University of Bonn, 53127, Bonn, Germany.; Institute of Human Genetics, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.; Division Neonatology and Pediatric Intensive Care, Department of Pediatric and Adolescent Medicine, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany., Odermatt B; Institute of Anatomy and Cell Biology, Medical Faculty, University of Bonn, 53115, Bonn, Germany. b.odermatt@uni-bonn.de.; Institute of Neuroanatomy, Medical Faculty, University of Bonn, 53115, Bonn, Germany. b.odermatt@uni-bonn.de.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2024 Oct 02; Vol. 14 (1), pp. 22909. Date of Electronic Publication: 2024 Oct 02.
DOI: 10.1038/s41598-024-74303-w
Abstrakt: Isl1 has been described as an embryonic master control gene expressed in the pericloacal mesenchyme. Deletion of Isl1 from the genital mesenchyme in mice leads to an ectopic urethral opening and epispadias-like phenotype. Using genome wide association methods, we identified ISL1 as the key susceptibility gene for classic bladder exstrophy (CBE), comprising epispadias and exstrophy of the urinary bladder. The most significant marker (rs6874700) identified in our recent GWAS meta-analysis achieved a p value of 1.48 × 10 - 24 within the ISL1 region. In silico analysis of rs6874700 and all other genome-wide significant markers in Linkage Disequilibrium (LD) with rs6874700 (D' = 1.0; R 2  > 0.90) revealed marker rs2303751 (p value 8.12 × 10 - 20 ) as the marker with the highest regulatory effect predicted. Here, we describe a novel 1.2 kb intragenic promoter residing between 6.2 and 7.4 kb downstream of the ISL1 transcription starting site, which is located in the reverse DNA strand and harbors a binding site for EZH2 at the exact region of marker rs2303751. We show, that EZH2 silencing in HEK cells reduces ISL1 expression. We show that ezh2 -/- knockout (KO) zebrafish larvae display tissues specificity of ISL1 regulation with reduced expression of Isl1 in the pronephric region of zebrafish larvae. In addition, a shorter and malformed nephric duct is observed in ezh2 -/- ko zebrafish Tg(wt1ß:eGFP) reporter lines. Our study shows, that Ezh2 is a key regulator of Isl1 during urinary tract formation and suggests tissue specific ISL1 dysregulation as an underlying mechanism for CBE formation.
(© 2024. The Author(s).)
Databáze: MEDLINE
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