Regulation of Kidney-Specific Gene Expression

肾脏特异性基因表达的调节

基本信息

批准号：
10629391
负责人：
Peter Igarashi
金额：
$ 48.03万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-11-18 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10629391
关键词：
Ablation Adhesives Affect Binding Biochemical CHD4 gene Cell Proliferation Cells ChIP-seq Chromatin Loop Chromatin Remodeling Factor Complex Couples Cyclic AMP Cyst Cystic Kidney Diseases DNA DNA Binding Deposition Disease Distal EZH2 gene Enhancers Epithelial Cells Epithelium Fibrosis Gene Expression Gene Expression Regulation Genes Genetic Genetic Transcription Genomics Goals Growth Health Hi-C Histone Acetylation Histones Human Immunoprecipitation Individual Inherited Kidney Kidney Diseases Kidney Failure Ligands Mass Spectrum Analysis Measures Messenger RNA Molecular Mus Mutant Strains Mice Mutation Names NuRD complex Organ Pathogenesis Pathway interactions Phenotype Phosphorylation Play Polycomb Polycystic Kidney Diseases Polymerase Proteins RNA Polymerase II Regulation Renal function Repression Role Signal Pathway Signal Transduction Structure Testing Tissue-Specific Gene Expression Transcription Elongation Transcriptional Regulation Untranslated RNA Urinary tract WNT Signaling Pathway WNT9A gene Wnt proteins Work autosome beta catenin chromatin modification chromatin remodeling chromosome conformation capture congenital anomalies of the kidney derepression fibrogenesis gene repression genome-wide hepatocyte nuclear factor histone methylation histone modification improved in vivo evaluation indexing insight interstitial kidney cell kidney fibrosis lipid metabolism lymphoid enhancer-binding factor 1 mouse genetics mouse model mutant mutant mouse model nephrogenesis novel overexpression palmitoylation promoter recruit renal epithelium therapeutic target trafficking transcription factor transcriptome sequencing urinary

项目摘要

ABSTRACT The purpose of this MERIT renewal is to continue our studies on hepatocyte nuclear factor-1β (HNF-1β) and its roles in kidney-specific gene expression and cystic kidney diseases. HNF-1β is a DNA-binding transcription factor that regulates tissue-specific gene expression in the kidney and other epithelial organs. Mutations of HNF- 1β produce congenital anomalies of the kidney and urinary tract, cystic kidney disease, autosomal dominant tubulointerstitial kidney disease, and inherited tubulopathies. To unravel the pathogenesis of these disorders, we have produced HNF-1β mutant mice that develop phenotypes similar to those seen in affected humans. Analysis of the mutant mice has revealed that HNF-1β plays a central role in the expression of polycystic kidney disease genes, such as PKD2 and PKHD1. During the last project period, we used genome-wide ChIP-seq and RNA-seq to identify transcriptional networks that are directly regulated by HNF-1β. Together with new mutant mouse models, these studies uncovered novel roles of HNF-1β in the regulation of Wnt signaling, cAMP signaling, lipid metabolism, urinary concentration, and expression of noncoding RNAs. Preliminary studies using mass spectrometry revealed that HNF-1β interacts with proteins involved in chromatin remodeling, histone modification, and transcription elongation. In the next project period we will extend this work to further unravel the functions of HNF-1β in the kidney. Specific Aim 1 will use biochemical studies to unravel the molecular mechanisms whereby HNF-1β represses Wnt pathway genes. We will test the hypothesis that HNF-1β forms repressive chromatin loops that exert long-range effects on histone modification, chromatin remodeling, and transcription elongation. Specific Aim 2 will apply mouse genetics to elucidate the roles of dysregulated Wnt signaling in the HNF-1β mutant phenotype. We will determine whether mutations of Wnt pathway genes that are overexpressed in HNF-1β mutant mice improve kidney function and structure. Collectively, the proposed studies will advance our understanding of gene regulation, unravel how mutations of HNF-1β produce kidney abnormalities, and identify potential therapeutic targets for HNF-1β-related cystic kidney diseases.

抽象的本次MERIT更新的目的是继续我们对肝细胞核因子-1β（HNF-1β）及其相关的研究 HNF-1β 是一种 DNA 结合转录，在肾脏特异性基因表达和囊性肾病中发挥作用。调节肾脏和其他上皮器官中组织特异性基因表达的因子。 1β 产生肾脏和泌尿道先天性异常、囊性肾病、常染色体显性遗传肾小管间质性肾病和遗传性肾小管病为了阐明这些疾病的发病机制，我们已经培育出 HNF-1β 突变小鼠，其表型与受影响的人类相似。对突变小鼠的分析表明，HNF-1β在多囊肾的表达中起着核心作用疾病基因，例如 PKD2 和 PKHD1 在上一个项目期间，我们使用了全基因组 ChIP-seq 和 RNA-seq 鉴定受 HNF-1β 和新突变体直接调控的转录网络。小鼠模型中，这些研究揭示了 HNF-1β 在 Wnt 信号传导、cAMP 调节中的新作用使用非编码 RNA 进行信号传导、脂质代谢、尿浓度和表达的初步研究。质谱分析显示 HNF-1β 与参与染色质重塑的蛋白质、组蛋白相互作用在下一个项目期间，我们将扩展这项工作以进一步阐明。 HNF-1β 在肾脏中的功能具体目标 1 将利用生化研究来阐明其分子机制。 HNF-1β 抑制 Wnt 通路基因的机制我们将检验 HNF-1β 形成的假设。抑制性染色质环对组蛋白修饰、染色质重塑和具体目标 2 将应用小鼠遗传学来阐明 Wnt 失调的作用。我们将确定 HNF-1β 突变表型中的信号传导是否是 Wnt 通路基因的突变。总的来说，拟议的研究在 HNF-1β 突变小鼠中过度表达可改善肾功能和结构。将增进我们对基因调控的理解，揭示 HNF-1β 突变如何产生肾脏异常，并确定 HNF-1β 相关囊性肾病的潜在治疗靶点。

项目成果

期刊论文数量（51）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Following the expression of a kidney-specific gene from early development to adulthood.

跟踪从早期发育到成年的肾脏特异性基因的表达。

DOI：
发表时间：
2003
期刊：
影响因子：
0
作者：
Igarashi; Peter
通讯作者：
Peter

Tissue-specific regulation of the mouse Pkhd1 (ARPKD) gene promoter.

小鼠 Pkhd1 (ARPKD) 基因启动子的组织特异性调控。

DOI：
发表时间：
2014-08-01
期刊：
影响因子：
0
作者：
Williams, Scott S;Cobo;Hajarnis, Sachin;Aboudehen, Karam;Shao, Xinli;Richardson, James A;Patel, Vishal;Igarashi, Peter
通讯作者：
Igarashi, Peter

microRNA-17 family promotes polycystic kidney disease progression through modulation of mitochondrial metabolism.

microRNA-17家族通过调节线粒体代谢促进多囊肾病的进展。

DOI：
发表时间：
2017
期刊：
影响因子：
16.6
作者：
Hajarnis, Sachin;Lakhia, Ronak;Yheskel, Matanel;Williams, Darren;Sorourian, Mehran;Liu, Xueqing;Aboudehen, Karam;Zhang, Shanrong;Kersjes, Kara;Galasso, Ryan;Li, Jian;Kaimal, Vivek;Lockton, Steven;Davis, Scott;Flaten, Andrea;Johnson, Joshua
通讯作者：
Johnson, Joshua

Role of transcription factor hepatocyte nuclear factor-1β in polycystic kidney disease.

转录因子肝细胞核因子-1β 在多囊肾病中的作用。

DOI：
10.1016/j.cellsig.2020.109568
发表时间：
2020-02-14
期刊：
Cellular signalling
影响因子：
4.8
作者：
Annie Shao;S. Chan;P. Igarashi
通讯作者：
P. Igarashi

HNF-1beta regulates transcription of the PKD modifier gene Kif12.

HNF-1beta 调节 PKD 修饰基因 Kif12 的转录。

DOI：
10.1681/asn.2008020238
发表时间：
2024-09-14
期刊：
Journal of the American Society of Nephrology : JASN
影响因子：
0
作者：
Yimei Gong;Zhendong Ma;V. Patel;Evelyne Fischer;T. Hiesberger;M. Pontoglio;P. Igarashi
通讯作者：
P. Igarashi