Mounting evidence indicates that alterations in chromatin structure and function induce specific and significant changes in gene expression. Histone deacetylases (HDACs) are an evolutionarily conserved class of enzymes which remove acetyl groups from histones and compacts the nucleosome and thus prevents access of DNA-binding proteins to DNA. Moreover, HDACs, along with histone methyltransferases and other histone modifiers, create an """"""""epigenetic code"""""""" that is read by transcriptional repressors or activators. Histone acetylation plays important roles in cancer, immune disorders and embryonic development. In the mouse, targeted inactivation of HDAC1 and HDAC2 genes causes embryonic lethality precluding the analysis of kidney development. The overall aim of this proposal is to elucidate the nephric lineage-specific functions of HDAC1/2. Our preliminary data indicate that HDAC 1 and HDAC2 are expressed in both compartments of the developing kidney, the metanephric mesenchyme (MM) and ureteric bud (UB), in a developmentally regulated manner. Pharmacological inhibition of metanephric HDAC activity induces lineage-specific and time-dependent changes in gene expression, compromises metanephric proliferation, and provokes premature differentiation. We therefore propose that HDAC 1 and HDAC 2 perform essential roles in the epigenetic control of kidney development: 1) in the MM, HDAC1/2 are required for maintained expression of the Eya1 and Foxd1 genes as well as survival and renewal of MM cells;2) in the UB, HDAC1/2 maintain the pool of tip Ret+/Wnt11+ cells and repress the terminal differentiation program. We will use a variety of genetic and biochemical approaches, together with organotypic and cell culture systems, to conduct the following specific aims: 1) Elucidate the developmental processes and lineage-specific morphogenetic pathways that are dependent on HDACs during metanephric development;2) Determine the contribution of HDAC1/2 to the regulation of the Gdnf-Ret-Wnt11 pathway;and 2) Identify HDAC-sensitive gene regulatory networks in the MM and UB lineages. The results will provide new insights into the epigenetic control of organogenesis and have important clinical implications as abnormal renal development is the leading cause of chronic renal failure in infants and children.
Congenital malformations of the kidney and urinary tract account for up to 40% of chronic kidney failure in children less than 4 years of age. In addition to mutations in the DNA sequence, abnormal kidney development may result from alterations in the """"""""epigenetic code"""""""" which lies in the proteins around which the DNA is wrapped in the nucleus of the cell. Stable alterations in the epigenetic code resulting from transient environmental exposures (e.g., toxins, drugs, viral infections) can disrupt fetal gene expression without altering the DNA sequence. Thus, understanding the epigenetic regulation of kidney development may open new avenues to the treatment or prevention of kidney and urinary tract malformations and kidney failure.
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