Epigenetic Regulation of Kidney Development

摘要

ABSTRACT Gene expression patterns define the differentiated state of cells and their physiological functions. During embryonic development, gene expression patterns are set, in part, by epigenetic modifications that compartmentalize the genome into active euchromatin and silent heterochromatin. These modifications include histone and DNA methylation, which imprint a unique cell-type specific pattern on the epigenome such that cellular fates and phenotypic stability are maintained. In diseased states, the normal pattern of gene expression is disturbed which can result in altered cellular function, growth deregulation, abnormal cell signaling, and cell death. This competitive renewal application proposes that epigenetic changes can underlie the alterations in gene expression patterns observed in both acute and chronic renal disease. In the previous funding period, the PI has identified Pax2 as a critical DNA binding protein in the renal epithelial lineage. The lab then discovered PTIP as an adaptor protein that links Pax2 to a histone methylation complex to imprint positive epigenetic marks on target genes. The PTIP protein interacts with a variety of DNA binding proteins to recruit an MLL3/4 histone H3K4 methyltransferase complex to chromatin. This Pax2/PTIP interaction can be inhibited by the repressor proteins of the Tle/Groucho family, which are expressed in more differentiated renal epithelial cells. The current application will address how epigenetic regulators impact the fate of renal epithelial cells and renal interstitial fibroblasts in both acute and chronic disease states. Preliminary data strongly suggests that epigenetic modifications are needed to reset the proper transcriptional program of a renal epithelial cell during regeneration after acute injury. Our first specific aim will address the need for epigenetic modifiers in promoting regeneration and maintaining renal epithelia after injury. The second aim will address changes in renal interstitial fibroblasts or stromal cells in response to acute or chronic injury. The expansion of fibroblasts and myofibroblasts is a common pathology observed in the kidney and other tissues in chronic, progressive diseases. Yet, in limited cases the fibrosis is reversible. The reversibility suggests some type of epigenetic memory that may be altered in the case of irreversible fibrotic disease. What are the differences in gene expression and epigenetic modifications between a myofibroblast that defines an irreversible, progressive disease state and one that can be reversible? The answers to this question will reveal potential novel pathways that control phenotypic stability, cell proliferation, and disease progression in a variety of abnormal states. Given the limited treatment options currently available for chronic renal disease, understanding the epigenetic level of control in the disease state is paramount for developing new therapeutic options.