Epigenetic Regulation of Kidney Development

摘要 基因表达模式定义了细胞的分化状态和它们的生理功能。 功能协调发展的在胚胎发育过程中，基因表达模式部分由以下因素决定： 表观遗传修饰，将基因组划分为活性常染色质， 沉默异染色质这些修饰包括组蛋白和DNA甲基化， 其在表观基因组上印记独特的细胞类型特异性模式， 维持命运和表型稳定性。在疾病状态下，正常的 基因表达受到干扰，这可能导致细胞功能、生长 失调、异常细胞信号传导和细胞死亡。这次竞争性的续约 应用程序提出，表观遗传变化可能是基因改变的基础， 在急性和慢性肾脏疾病中观察到的表达模式。上一 在资助期间，PI已将Pax 2确定为肾脏中的关键DNA结合蛋白。 上皮细胞系然后，实验室发现PTIP是一种衔接蛋白， 一种组蛋白甲基化复合物，在靶基因上留下阳性表观遗传标记。的 PTIP蛋白与多种DNA结合蛋白相互作用以募集MLL 3/4组蛋白 H3 K4甲基转移酶复合物与染色质。这种Pax 2/PTIP相互作用可以是 被Tle/Groucho家族的阻遏蛋白抑制，其表达于 更分化的肾上皮细胞。当前的应用程序将解决如何 表观遗传调节因子影响肾上皮细胞和肾间质的命运 成纤维细胞在急性和慢性疾病状态。初步数据显示 表观遗传修饰需要重新设置正常的转录程序， 急性损伤后肾上皮细胞再生过程中。我们的第一个具体目标是 解决了表观遗传修饰剂在促进再生和维持 损伤后的肾上皮。第二个目标是解决肾间质的变化， 成纤维细胞或基质细胞响应急性或慢性损伤。扩大 成纤维细胞和肌成纤维细胞的损伤是在肾脏和其他组织中观察到的常见病理学。 慢性进行性疾病中的组织。然而，在有限的情况下，纤维化是可逆的。 这种可逆性表明，某种类型的表观遗传记忆可能会在 不可逆纤维化疾病的病例。在基因表达和 肌成纤维细胞之间的表观遗传修饰， 进行性疾病状态和一个可以是可逆的？对这个问题的回答 将揭示控制表型稳定性，细胞增殖， 和疾病进展的各种异常状态。考虑到有限的治疗 目前可用于慢性肾脏疾病的选择，了解表观遗传水平 疾病状态的控制对于开发新的治疗选择是至关重要的。

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.