Epigenetic Regulation of Kidney Development

摘要 基因表达模式定义了细胞的分化状态及其生理 功能。在胚胎发育期间，基因表达模式在一定程度上是通过 表观遗传修饰，将基因组分割成活性常染色质和 沉默的异染色质。这些修饰包括组蛋白和DNA甲基化， 它在表观基因组上印记一种独特的细胞类型特定模式，从而使细胞 命运和表型稳定性保持不变。在疾病状态下，正常的 基因表达紊乱，可能导致细胞功能、生长 放松管制，细胞信号异常，细胞死亡。这是一次竞争性更新 应用研究表明，表观遗传变化可能是基因变化的基础 在急性和慢性肾脏疾病中观察到的表达模式。在上一次 在资助期内，PI已经确定Pax2是肾脏中的关键DNA结合蛋白 上皮谱系。实验室随后发现PTIP是一种连接Pax2和Pax2的接头蛋白 一种组蛋白甲基化复合体，将阳性表观遗传标记印记在目标基因上。这个 PTIP蛋白与多种DNA结合蛋白相互作用募集MLL3/4组蛋白 H3K4甲基转移酶复合体为染色质。此Pax2/PTIP交互可以是 被TLE/Groucho家族的抑制蛋白抑制，这些抑制蛋白在 分化更多的肾上皮细胞。当前的应用程序将解决如何 表观遗传调节因子对肾上皮细胞和肾间质命运的影响 急慢性疾病状态下的成纤维细胞。初步数据强烈表明 表观遗传修饰是需要重置正确的转录程序的 急性损伤后再生过程中的肾上皮细胞。我们的第一个具体目标是 解决在促进再生和维持方面对表观遗传修饰物的需求 损伤后的肾上皮细胞。第二个目标是解决肾间质的变化。 成纤维细胞或基质细胞对急性或慢性损伤的反应。的扩展 成纤维细胞和肌成纤维细胞是肾脏和其他组织常见的病理改变。 慢性进行性疾病中的组织。然而，在极少数情况下，纤维化是可逆的。 这种可逆性暗示着某种类型的表观遗传记忆可能在 1例不可逆转的纤维性疾病。基因表达和基因表达有什么不同 在肌成纤维细胞之间的表观遗传修饰定义了不可逆转的， 进展性疾病状态和可逆状态？这个问题的答案是 将揭示控制表型稳定性、细胞增殖、 以及疾病在各种异常状态下的发展。考虑到有限的治疗 目前可用于慢性肾脏疾病的选择，了解表观遗传学水平 在疾病状态下的控制对于开发新的治疗方案至关重要。

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.