Epigenetic mechanisms of gene regulation in nephron progenitor cell proliferation and differentiation

肾单位祖细胞增殖和分化基因调控的表观遗传机制

基本信息

  • 批准号:
    10442628
  • 负责人:
  • 金额:
    $ 42.22万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-07-01 至 2026-06-30
  • 项目状态:
    未结题

项目摘要

The long-term goal of the proposed work is to determine mechanisms that control gene regulatory networks to generate a normal endowment of mature nephrons. Formation of the proper complement of nephrons requires a balance between self-renewal and differentiation of progenitor cells. Disruption of this balance leads to renal hypoplasia and chronic kidney disease. Soon after progenitor cells begin to differentiate, chromatin must undergo significant changes to set up gene expression patterns for formation of distinct cell types along the nephron. Defects in formation of specific renal epithelial cell types leads to glomerular disease and an inability of tubules to perform normal physiological functions, such as maintaining salt and water balance. A major mechanism by which cells respond to signals to direct gene expression to a particular fate or lineage is through the concerted action of chromatin remodeling complexes and tissue restricted transcription factors. These proteins act on regulatory regions in the genome to establish control of gene expression at the correct time and place. While individual factors that control gene expression in nephron progenitor cells have been defined, how these proteins cooperate to control gene expression in the developing kidney has not been explored. The identification and characterization of the regulatory elements where these factors act is also a major challenge in the field. We discovered that Sall1 plays a pivotal role in these developmental decisions by interacting with two distinct chromatin remodeling complexes, the Nucleosome Remodeling and Deacetylase (NuRD) complex and the Switch/Sucrose Non-Fermentable (SWI/SNF) complex. We propose that the integrated actions of Sall1, Six2, NuRD and SWI/SNF controls nephron progenitor cell gene expression to attain a dynamic balance between self-renewal and differentiation, and establishes the epigenetic modifications required for formation of specific cell lineages in the mature kidney. This novel paradigm will be tested in three Aims. In Aim 1, we will perform Hi-ChIP to identify enhancer-promoter contacts in uncommitted and induced progenitors, and define changes in mutant cells. Aim 2 will determine how genomic binding of Sall1, Six2, NuRD and SWI/SNF are affected in mutant nephron progenitor cells. Epigenomic editing will be used to demonstrate causal relationships between gene expression and binding of these factors at regulatory regions. In order to translate our findings to human development and disease, in Aim 3 we will test our findings in the mouse from Aims 1 and 2 in human iPS cell-derived nephron progenitor cells. These studies will illuminate mechanisms that underlie human genetic syndromes and sporadic birth defects, such as renal hypoplasia, which commonly cause childhood kidney failure. Our findings will also provide insight into how to reprogram kidney cells from a differentiated state back to a progenitor state, to promote regeneration of mature tubular epithelial cells in order to correct nephron deficits.
这项工作的长期目标是确定控制基因调控网络的机制 以产生正常的成熟肾单位。肾单位固有补体的形成 需要祖细胞的自我更新和分化之间的平衡。打破这种平衡, 肾发育不全和慢性肾病。在祖细胞开始分化后不久, 必须经历显著的变化,以建立基因表达模式,从而形成不同的细胞类型,沿着 肾单位特定肾上皮细胞类型形成的缺陷导致肾小球疾病, 肾小管不能执行正常的生理功能,如维持盐和水的平衡。 细胞对信号作出反应的一种主要机制,将基因表达导向特定的命运或 谱系是通过染色质重塑复合物和组织限制性转录的协同作用 因素这些蛋白质作用于基因组中的调节区域,以在细胞中建立对基因表达的控制。 正确的时间和地点。虽然控制肾单位祖细胞基因表达的个体因素 虽然这些蛋白质已经被定义,但这些蛋白质如何合作来控制发育中的肾脏中的基因表达还没有被确定。 探讨了这些因子发挥作用的调节元件的识别和表征也是一个 外地的重大挑战。 我们发现,Sall 1通过与两个基因相互作用,在这些发育决定中起着关键作用。 不同的染色质重塑复合物,核小体重塑和脱乙酰酶(NuRD)复合物, Switch/Sucrose Non-Fermentable(SWI/SNF)复合物。我们建议Sall 1, Six 2、NuRD和SWI/SNF调控肾单位祖细胞基因表达达到动态平衡 之间的自我更新和分化,并建立了形成所需的表观遗传修饰, 成熟肾脏中的特定细胞谱系。这一新的范例将在三个目标中得到检验。在目标1中,我们 进行Hi-ChIP以鉴定未定型和诱导祖细胞中的增强子-启动子接触,并确定 突变细胞的变化。目的2将确定Sall 1、Six 2、NuRD和SWI/SNF的基因组结合是如何进行的。 在突变的肾单位祖细胞中受到影响。表观基因组编辑将用于证明因果关系 基因表达与这些因子在调控区的结合之间的关系。在便转化 我们的发现对人类发育和疾病的影响,在目标3中,我们将在目标1的小鼠中测试我们的发现 和2在人iPS细胞衍生的肾单位祖细胞中。 这些研究将阐明人类遗传综合征和零星出生的机制 缺陷,如肾发育不全,这通常会导致儿童肾衰竭。我们的发现也将 深入了解如何将肾细胞从分化状态重编程回到祖细胞状态, 促进成熟肾小管上皮细胞的再生,以纠正肾单位缺陷。

项目成果

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MICHAEL I RAUCHMAN其他文献

MICHAEL I RAUCHMAN的其他文献

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{{ truncateString('MICHAEL I RAUCHMAN', 18)}}的其他基金

Research Project 2: Molecular analysis of developing post-natal mouse kidney in health and FSGS
研究项目2:健康和FSGS中小鼠产后肾脏发育的分子分析
  • 批准号:
    10530271
  • 财政年份:
    2022
  • 资助金额:
    $ 42.22万
  • 项目类别:
Research Project 2: Molecular analysis of developing post-natal mouse kidney in health and FSGS
研究项目2:健康和FSGS中小鼠产后肾脏发育的分子分析
  • 批准号:
    10707966
  • 财政年份:
    2022
  • 资助金额:
    $ 42.22万
  • 项目类别:
Single Cell Chromatin Profiling in Kidney Tissue
肾脏组织中的单细胞染色质分析
  • 批准号:
    10373426
  • 财政年份:
    2021
  • 资助金额:
    $ 42.22万
  • 项目类别:
Epigenetic mechanisms of gene regulation in nephron progenitor cell proliferation and differentiation
肾单位祖细胞增殖和分化基因调控的表观遗传机制
  • 批准号:
    10289761
  • 财政年份:
    2021
  • 资助金额:
    $ 42.22万
  • 项目类别:
Epigenetic mechanisms of gene regulation in nephron progenitor cell proliferation and differentiation
肾单位祖细胞增殖和分化基因调控的表观遗传机制
  • 批准号:
    10672271
  • 财政年份:
    2021
  • 资助金额:
    $ 42.22万
  • 项目类别:
Regulation of Nephron Progenitor Cell Self-Renewal and Differentiation
肾单位祖细胞自我更新和分化的调节
  • 批准号:
    9607382
  • 财政年份:
    2018
  • 资助金额:
    $ 42.22万
  • 项目类别:
Mechanisms and Treatment of Kidney Fibrosis
肾脏纤维化的机制和治疗
  • 批准号:
    10660981
  • 财政年份:
    2018
  • 资助金额:
    $ 42.22万
  • 项目类别:
Regulation of Nephron Progenitor Cell Self-Renewal and Differentiation
肾单位祖细胞自我更新和分化的调节
  • 批准号:
    9258431
  • 财政年份:
    2014
  • 资助金额:
    $ 42.22万
  • 项目类别:
Regulation of Nephron Progenitor Cell Self-Renewal and Differentiation
肾单位祖细胞自我更新和分化的调节
  • 批准号:
    8638282
  • 财政年份:
    2014
  • 资助金额:
    $ 42.22万
  • 项目类别:
Regulation of Nephron Progenitor Cell Self-Renewal and Differentiation
肾单位祖细胞自我更新和分化的调节
  • 批准号:
    8908006
  • 财政年份:
    2014
  • 资助金额:
    $ 42.22万
  • 项目类别:

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