Histone Deacetylase (HDAC) Activity Is Critical for Embryonic Kidney Gene Expression, Growth, and Differentiation*

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.

[1]  L. Lum,et al.  Canonical Wnt9b signaling balances progenitor cell expansion and differentiation during kidney development , 2011, Development.

[2]  J. Byrd,et al.  Histone Deacetylase Inhibitors Stimulate Histone H3 Lysine 4 Methylation in Part Via Transcriptional Repression of Histone H3 Lysine 4 Demethylases , 2011, Molecular Pharmacology.

[3]  N. Hukriede,et al.  Inhibition of histone deacetylase expands the renal progenitor cell population. , 2010, Journal of the American Society of Nephrology : JASN.

[4]  Wa Shen,et al.  Semaphorin3a regulates endothelial cell number and podocyte differentiation during glomerular development , 2009, Development.

[5]  Z. Saifudeen,et al.  p53 regulates metanephric development. , 2009, Journal of the American Society of Nephrology : JASN.

[6]  S. Arber,et al.  Etv4 and Etv5 are required downstream of GDNF and Ret for kidney branching morphogenesis , 2009, Nature Genetics.

[7]  E. Olson,et al.  Epigenetic control of skull morphogenesis by histone deacetylase 8. , 2009, Genes & development.

[8]  K. Reidy,et al.  Cell and molecular biology of kidney development. , 2009, Seminars in nephrology.

[9]  G. Chaturvedi,et al.  The homeodomain protein Cux1 interacts with Grg4 to repress p27 kip1 expression during kidney development. , 2009, Gene.

[10]  Monalee Saha,et al.  Role of Fibroblast Growth Factor Receptor 2 in Kidney Mesenchyme , 2008, Pediatric Research.

[11]  K. Schmidt-Ott,et al.  WNT/beta-catenin signaling in nephron progenitors and their epithelial progeny. , 2008, Kidney international.

[12]  J. Gómez-Skarmeta,et al.  A dual requirement for Iroquois genes during Xenopus kidney development , 2008, Development.

[13]  A. McMahon,et al.  Six2 defines and regulates a multipotent self-renewing nephron progenitor population throughout mammalian kidney development. , 2008, Cell stem cell.

[14]  N. Rosenblum.  Developmental biology of the human kidney. , 2008, Seminars in fetal & neonatal medicine.

[15]  N. Rosenblum,et al.  Canonical WNT/beta-catenin signaling is required for ureteric branching. , 2008, Developmental biology.

[16]  D. Cortez,et al.  Deletion of histone deacetylase 3 reveals critical roles in S phase progression and DNA damage control. , 2008, Molecular cell.

[17]  A. McMahon,et al.  Beta-catenin is necessary to keep cells of ureteric bud/Wolffian duct epithelium in a precursor state. , 2008, Developmental biology.

[18]  Catharine L. Smith.  A shifting paradigm: histone deacetylases and transcriptional activation , 2008, BioEssays : news and reviews in molecular, cellular and developmental biology.

[19]  D. Raciti,et al.  The prepattern transcription factor Irx3 directs nephron segment identity. , 2007, Genes & development.

[20]  G. Dressler,et al.  A Hox-Eya-Pax Complex Regulates Early Kidney Developmental Gene Expression , 2007, Molecular and Cellular Biology.

[21]  J. Schanstra,et al.  Gene expression profiling in the remnant kidney model of wild type and kinin B1 and B2 receptor knockout mice. , 2007, Kidney international.

[22]  Xiaoxia Qi,et al.  Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility. , 2007, Genes & development.

[23]  Raphael Kopan,et al.  Molecular insights into segmentation along the proximal-distal axis of the nephron. , 2007, Journal of the American Society of Nephrology : JASN.

[24]  R. Behringer,et al.  Laser capture‐microarray analysis of Lim1 mutant kidney development , 2007, Genesis.

[25]  Z. Saifudeen,et al.  The Bradykinin B2 receptor gene is a target of angiotensin II type 1 receptor signaling. , 2007, Journal of the American Society of Nephrology : JASN.

[26]  W. Wurst,et al.  Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3β activity , 2007, Nature Medicine.

[27]  A. McMahon,et al.  Notch2, but not Notch1, is required for proximal fate acquisition in the mammalian nephron , 2007, Development.

[28]  J. Mehnert,et al.  Histone Deacetylase Inhibitors: Biology and Mechanism of Action , 2007, Cancer journal.

[29]  J. Licht,et al.  Branching morphogenesis of the ureteric epithelium during kidney development is coordinated by the opposing functions of GDNF and Sprouty1. , 2006, Developmental biology.

[30]  G. Dressler,et al.  Six2 is required for suppression of nephrogenesis and progenitor renewal in the developing kidney , 2006, The EMBO journal.

[31]  G. Dressler.  The cellular basis of kidney development. , 2006, Annual review of cell and developmental biology.

[32]  Frank Costantini,et al.  Renal branching morphogenesis: concepts, questions, and recent advances. , 2006, Differentiation; research in biological diversity.

[33]  E. Olson,et al.  Histone Deacetylase 7 Maintains Vascular Integrity by Repressing Matrix Metalloproteinase 10 , 2006, Cell.

[34]  M. D. de Caestecker,et al.  Role of transcriptional networks in coordinating early events during kidney development. , 2006, American journal of physiology. Renal physiology.

[35]  Richard R Behringer,et al.  Gene expression profiles in developing nephrons using Lim1 metanephric mesenchyme-specific conditional mutant mice , 2006, BMC nephrology.

[36]  Sharon Y. R. Dent,et al.  Histone modifying enzymes and cancer: Going beyond histones , 2005, Journal of cellular biochemistry.

[37]  M. Taglienti,et al.  Angioblast-mesenchyme induction of early kidney development is mediated by Wt1 and Vegfa , 2005, Development.

[38]  S. Grimmond,et al.  Temporal and spatial transcriptional programs in murine kidney development. , 2005, Physiological genomics.

[39]  A. McMahon,et al.  Wnt9b plays a central role in the regulation of mesenchymal to epithelial transitions underlying organogenesis of the mammalian urogenital system. , 2005, Developmental cell.

[40]  A. McMahon,et al.  Distinct and sequential tissue-specific activities of the LIM-class homeobox gene Lim1 for tubular morphogenesis during kidney development , 2005, Development.

[41]  Andrew J. Wilson,et al.  Gene expression profiling of intestinal epithelial cell maturation along the crypt-villus axis. , 2005, Gastroenterology.

[42]  N. Manley,et al.  Differential expression of Sonic hedgehog along the anterior-posterior axis regulates patterning of pharyngeal pouch endoderm and pharyngeal endoderm-derived organs. , 2005, Developmental biology.

[43]  John M. Shelton,et al.  Histone Deacetylase 4 Controls Chondrocyte Hypertrophy during Skeletogenesis , 2004, Cell.

[44]  E. Olson,et al.  Histone Deacetylases 5 and 9 Govern Responsiveness of the Heart to a Subset of Stress Signals and Play Redundant Roles in Heart Development , 2004, Molecular and Cellular Biology.

[45]  A. McMahon,et al.  Recent genetic studies of mouse kidney development. , 2004, Current opinion in genetics & development.

[46]  S. Sakamoto,et al.  Histone Deacetylase Activity Is Required to Recruit RNA Polymerase II to the Promoters of Selected Interferon-stimulated Early Response Genes* , 2004, Journal of Biological Chemistry.

[47]  M. Bouchard.  Transcriptional control of kidney development. , 2004, Differentiation; research in biological diversity.

[48]  V. Castronovo,et al.  Expression of histone deacetylase 8, a class I histone deacetylase, is restricted to cells showing smooth muscle differentiation in normal human tissues. , 2004, The American journal of pathology.

[49]  Frank Costantini,et al.  Real-time analysis of ureteric bud branching morphogenesis in vitro. , 2004, Developmental biology.

[50]  C. Petit,et al.  SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[51]  R. Shivdasani,et al.  Regulation of Mammalian Epithelial Differentiation and Intestine Development by Class I Histone Deacetylases , 2004, Molecular and Cellular Biology.

[52]  L. Ngo,et al.  Histone deacetylase (HDAC) inhibitor activation of p21WAF1 involves changes in promoter-associated proteins, including HDAC1. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[53]  T. Noda,et al.  Crucial roles of Brn1 in distal tubule formation and function in mouse kidney , 2003, Development.

[54]  H. Sakurai.  Molecular mechanism of ureteric bud development. , 2003, Seminars in cell & developmental biology.

[55]  R. Currie,et al.  Histone deacetylase inhibition is associated with transcriptional repression of the Hmga2 gene. , 2003, Nucleic acids research.

[56]  Sube Banerjee,et al.  Histone acetylation-mediated regulation of genes in leukaemic cells , 2003 .

[57]  A. V. van Kuilenburg,et al.  Histone deacetylases (HDACs): characterization of the classical HDAC family. , 2003, The Biochemical journal.

[58]  Dimitris Thanos,et al.  Deciphering the Transcriptional Histone Acetylation Code for a Human Gene , 2002, Cell.

[59]  D. O’Carroll,et al.  Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression , 2002, The EMBO journal.

[60]  M. Capecchi,et al.  Hox11 paralogous genes are essential for metanephric kidney induction. , 2002, Genes & development.

[61]  D. Witte,et al.  Microarray analysis of novel cell lines representing two stages of metanephric mesenchyme differentiation , 2002, Mechanisms of Development.

[62]  Joe C. Adams,et al.  Eya1-deficient mice lack ears and kidneys and show abnormal apoptosis of organ primordia , 1999, Nature Genetics.

[63]  E. Robertson,et al.  Interaction between FGF and BMP signaling pathways regulates development of metanephric mesenchyme. , 1999, Genes & development.

[64]  C. Hui,et al.  Developmentally regulated expression of the transcriptional cofactors/histone acetyltransferases CBP and p300 during mouse embryogenesis. , 1999, The International journal of developmental biology.

[65]  M Aguet,et al.  VEGF is required for growth and survival in neonatal mice. , 1999, Development.

[66]  S. Aizawa,et al.  Defects of urogenital development in mice lacking Emx2. , 1997, Development.

[67]  Jonas Frisén,et al.  Renal agenesis and the absence of enteric neurons in mice lacking GDNF , 1996, Nature.

[68]  Mart Saarma,et al.  Defects in enteric innervation and kidney development in mice lacking GDNF , 1996, Nature.

[69]  P. Gruss,et al.  Pax-2 controls multiple steps of urogenital development. , 1995, Development.

[70]  David Housman,et al.  WT-1 is required for early kidney development , 1993, Cell.

[71]  C. Grobstein.  Inductive epitheliomesenchymal interaction in cultured organ rudiments of the mouse. , 1953, Science.

[72]  E. Olson,et al.  The many roles of histone deacetylases in development and physiology: implications for disease and therapy , 2009, Nature Reviews Genetics.

[73]  Y. Mishina,et al.  BMP receptor ALK3 controls collecting system development. , 2008, Journal of the American Society of Nephrology : JASN.

[74]  S. Vainio,et al.  Organogenesis: Coordinating early kidney development: lessons from gene targeting , 2002, Nature Reviews Genetics.

[75]  Vivette D. D’Agati,et al.  Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. , 1999, Developmental genetics.

[76]  E. Robertson,et al.  Role of BMP family members during kidney development. , 1999, The International journal of developmental biology.

[77]  C. Van Lint,et al.  The expression of a small fraction of cellular genes is changed in response to histone hyperacetylation. , 1996, Gene expression.