title: Histone deacetylase (HDAC) activity is critical for embryonic kidney gene expression, growth, and differentiation.
abstract: Histone deacetylases (HDACs) regulate fundamental biological processes such as cellular proliferation, differentiation, and survival via genomic and nongenomic effects. This study examined the importance of HDAC activity in the regulation of gene expression and differentiation of the developing mouse kidney. Class I HDAC1-3 and class II HDAC4, -7, and -9 genes are developmentally regulated. Moreover, HDAC1-3 are highly expressed in nephron precursors. Short term treatment of cultured mouse embryonic kidneys with HDAC inhibitors (HDACi) induced global histone H3 and H4 hyperacetylation and H3K4 hypermethylation. However, genome-wide profiling revealed that the HDAC-regulated transcriptome is restricted and encompasses regulators of the cell cycle, Wnt/β-catenin, TGF-β/Smad, and PI3K-AKT pathways. Further analysis demonstrated that base-line expression of key developmental renal regulators, including Osr1, Eya1, Pax2/8, WT1, Gdnf, Wnt9b, Sfrp1/2, and Emx2, is dependent on intact HDAC activity. Treatment of cultured embryonic kidney cells with HDACi recapitulated these gene expression changes, and chromatin immunoprecipitation assays revealed that HDACi is associated with histone hyperacetylation of Pax2/Pax8, Gdnf, Sfrp1, and p21. Gene knockdown studies demonstrated that HDAC1 and HDAC2 play a redundant role in regulation of Pax2/8 and Sfrp1 but not Gdnf. Long term treatment of embryonic kidneys with HDACi impairs the ureteric bud branching morphogenesis program and provokes growth arrest and apoptosis. We conclude that HDAC activity is critical for normal embryonic kidney homeostasis, and we implicate class I HDACs in the regulation of early nephron gene expression, differentiation, and survival.
authors.affiliation: Department of Pediatrics, Section of Pediatric Nephrology, Tulane University Health Sciences Center, New Orleans, Louisiana 70112, USA.
authors.forename: Shaowei
authors.initials: S
authors.lastname: Chen
authors.forename: Christine
authors.initials: C
authors.lastname: Bellew
authors.forename: Xiao
authors.initials: X
authors.lastname: Yao
authors.forename: Jana
authors.initials: J
authors.lastname: Stefkova
authors.forename: Susana
authors.initials: S
authors.lastname: Dipp
authors.forename: Zubaida
authors.initials: Z
authors.lastname: Saifudeen
authors.forename: Dimcho
authors.initials: D
authors.lastname: Bachvarov
authors.forename: Samir S
authors.initials: SS
authors.lastname: El-Dahr
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D004622:Embryo, Mammalian / Q000166:cytology / Q000201:enzymology*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D007668:Kidney / Q000166:cytology / Q000196:embryology* / Q000201:enzymology; D051379:Mice; D008822:Mice, Transgenic; D009024:Morphogenesis / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D014157:Transcription Factors; D006655:Histone Deacetylases