The role of histone deacetylases in kidney development.

摘要

Epigenetic mechanisms play a key role in the control of gene expression and cell fate decisions. Histone deacetylases (HDACs) are a conserved group of epigenetic regulators and chromatin remodelers. While the critical role of HDACs in cancer and immune disorders is increasingly recognized, their role in organogenesis remains largely unknown. The present study investigates the developmental biology of Hdacs in the mouse metanephric kidney. We demonstrate that Class I Hdac genes are highly expressed during nephrogenesis and ureteric bud branching morphogenesis, and are downregulated postnatally. Whereas Class I Hdacs are enriched in the epithelial and mesenchyme cell lineages, Class II Hdacs are predominantly vascular. Utilizing distinct classes of HDAC inhibitors, we demonstrate that Hdacs regulate the master developmental programs of metanephric development. The Hdac-regulated transcriptome encompasses regulators of the cell cycle, Wnt/beta-catenin, TGF-beta/Smad and PI3K-Akt pathways. In the metanephric mesenchyme, the Osr1/Eya1/Pax2/Hox11/WT1 regulatory network is a primary target of Hdac activity. In the ureteric bud lineage, Wnt9b, Spry1 and Emx2 are among the Hdac-target genes. Consistent with these findings, expression of c-Myc, Cnd1, Axin2, Fgf8, Pax8, Wnt4, and Lhx1 genes is highly dependent on Hdac activity. Persistent inhibition of metanephric Hdac activity culminates in irreversible growth arrest and apoptosis. Gene knockdown in the metanephric mesenchyme cell line MK4 confirmed a cell-autonomous role for Hdac1 and Hdac2 in regulation of Pax2, Pax8, Sfrp1, and Wnt4 gene expression. Collectively, these data demonstrate that Hdacs are critical epigenetic regulators of metanephric gene expression, cell proliferation, and survival.