Role of the Rett Syndrome-causing gene MeCP2 in 3D chromosomal organization and rescue of cellular disease phenotypes

Rett 综合征致病基因 MeCP2 在 3D 染色体组织和细胞疾病表型拯救中的作用

基本信息

  • 批准号:
    10065818
  • 负责人:
  • 金额:
    $ 24.31万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-04-01 至 2023-01-31
  • 项目状态:
    已结题

项目摘要

Modified Project Summary/Abstract Section As an NIH Pathway to Independence K99/R00 awardee, I am moving to Columbia University Medical Center to start my research laboratory as a principle investigator for the R00 phase. Rett syndrome (RTT) is an X-linked postnatal progressive neurodevelopmental disorder associated with severe mental disability and autism-like syndromes. The disease is caused by loss-of-function mutations of the DNA binding protein MeCP2 (Methyl CpG-binding Protein 2) in the X chromosome and represents the second most common cause of intellectual disability in females. Loss of MeCP2 leads to expression changes in thousands of genes, compromises the majority of brain cells and circuits, and dysregulates all neurotransmitter systems. However, how MeCP2 can act as a global repressor of gene activity as well as an activator for gene expression remains an open question in the field. Microcephaly (the reduction in brain size) has been documented as a hallmark of RTT, and analysis of hESC/iPSC-derived RTT neurons showed a reduced soma size as well. Our preliminary studies on human RTT mutant neurons showed a panel of cellular phenotypes including reduced soma size, impaired electrical properties, and defects in chromosomal structures. Therefore, we hypothesized that MeCP2 is involved in the organization of 3D chromosomal landscape contributing to the regulation of gene expression and subsequent neurobiology. We demonstrated that MeCP2 proteins form dynamic liquid-like condensates at the heterochromatic regions and concentrate heterochromatic factor HP1α but not components of active transcription in the nucleus. This condensate property of MeCp2 contributes to the compartmentation of 3D genome and the regulation of transcription machinery (Aim 1, K99 phase). Then we found that the intrinsically disordered region-2 (IDR-2) of MeCP2 protein mediates the formation of heterochromatin condensate. A common RTT mutant MeCP2-R168X lacking IDR-2 fails to form heterochromatin condensates to concentrate the heterochromatic factor and causes defects in the transcription regulation, providing a molecular mechanism of MeCP2-mediated 3D chromosomal organization (Aim 2, K99 phase). Development of RTT-like symptoms in mice can be reversed in RTT adult animals following the restoration of MeCP2 expression. As most female RTT patients still carry a wild type allele of MeCP2 subject to the random X-chromosome inactivation (XCI), it will be of therapeutic benefit if the wild type allele of MeCp2 in the inactive X chromosome (Xi) can be reactivated. We developed a DNA methylation editing tool by fusion of a catalytically inactive Cas9 with Tet1/Dnmt3a. Recently we expanded this toolbox to manipulate other epigenetic modifications including histone acetylation and DNA looping. We will use these tools to reverse the RTT phenotypes via reactivation of the wild type MECP2 allele on the Xi (Aim 3, R00 phase).This project will fill the gaps in our knowledge of MeCP2 function in the organization of 3D chromosomal structure and test the novel therapeutic approach to reverse RTT phenotypes.
修改后的项目摘要/摘要部分 作为 NIH 独立之路 K99/R00 获奖者,我将前往哥伦比亚大学医学中心开始我的研究实验室,担任 R00 阶段的首席研究员,这是一种 X 连锁的产后进行性神经发育障碍,与严重的相关。该疾病是由 X 染色体 DNA 结合蛋白 MeCP2(甲基 CpG 结合蛋白 2)功能丧失突变引起的,是第二常见的原因。 MeCP2 的缺失会导致数千个基因的表达变化,损害大多数脑细胞和回路,并使所有神经递质系统失调。然而,MeCP2 如何充当基因活动的全局抑制因子。基因表达的激活剂仍然是该领域的一个悬而未决的问题,小头畸形(大脑尺寸减小)已被记录为 RTT 的标志,对 hESC/iPSC 衍生的 RTT 神经元的分析表明。我们对人类 RTT 突变神经元的初步研究显示了一系列细胞表型,包括胞体大小减小、电特性受损和染色体结构缺陷,因此,我们发现 MeCP2 参与了 3D 染色体景观的组织。我们证明 MeCP2 蛋白在异染色质区域形成动态液体状凝聚物,并浓缩异染色质因子 HP1α,但不浓缩异染色质区域中的活性转录成分。 MeCp2 的这种凝聚特性有助于 3D 基因组的划分和转录机制的调节(目标 1,K99 阶段),然后我们发现 MeCP2 蛋白的本质无序区域 2 (IDR-2) 介导了 3D 基因组的形成。缺乏IDR-2的常见RTT突变体MeCP2-R168X无法形成异染色质凝聚物来浓缩异染色质因子并导致转录调控中的缺陷,提供了 MeCP2 介导的 3D 染色体组织(Aim 2,K99 期)的分子机制,在 RTT 成年动物中,在 MeCP2 表达恢复后,小鼠中 RTT 样症状的发展可以逆转。 RTT 患者仍携带 MeCP2 野生型等位基因,但会受到随机 X 染色体失活 (XCI) 的影响,如果患者体内存在 MeCp2 野生型等位基因,将具有治疗益处。失活的 X 染色体 (Xi) 可以重新激活,通过将催化失活的 Cas9 与 Tet1/Dnmt3a 融合,我们开发了一种 DNA 甲基化编辑工具。通过重新激活 Xi 上的野生型 MECP2 等位基因(目标 3,R00 阶段)来逆转 RTT 表型的工具。该项目将填补我们对 MeCP2 在 3D 染色体结构组织中的功能的了解存在差距,并测试逆转 RTT 表型的新治疗方法。

项目成果

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X. Shawn Liu其他文献

A serotonin receptor antagonist induces oocyte maturation in both frogs and mice: Evidence that the same G protein‐coupled receptor is responsible for maintaining meiosis arrest in both species
血清素受体拮抗剂诱导青蛙和小鼠的卵母细胞成熟:证据表明相同的 G 蛋白偶联受体负责维持两个物种的减数分裂停滞
  • DOI:
    10.1002/jcp.20170
  • 发表时间:
    2005-03-01
  • 期刊:
  • 影响因子:
    5.6
  • 作者:
    Y. Sheng;Ling Wang;X. Shawn Liu;Véronique Montplaisir;M. Tiberi;J. Baltz;X. J. Liu
  • 通讯作者:
    X. J. Liu

X. Shawn Liu的其他文献

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{{ truncateString('X. Shawn Liu', 18)}}的其他基金

Epigenetic mechanisms contributing to the pathogenesis of ALS/FTD with GGGGCC repeat expansion mutation at the C9orf72 locus
C9orf72 基因座 GGGGCC 重复扩增突变导致 ALS/FTD 发病的表观遗传机制
  • 批准号:
    10412699
  • 财政年份:
    2022
  • 资助金额:
    $ 24.31万
  • 项目类别:
Epigenetic Mechanisms Contributing to the Pathogenesis of ALS/FTD with GGGGCC Repeat Expansion Mutation at the C9orf72 Locus
C9orf72 基因座 GGGGCC 重复扩增突变导致 ALS/FTD 发病机制的表观遗传机制
  • 批准号:
    10792462
  • 财政年份:
    2022
  • 资助金额:
    $ 24.31万
  • 项目类别:
Role of the Rett Syndrome-causing gene MeCP2 in 3D chromosomal organization and rescue of cellular disease phenotypes
Rett 综合征致病基因 MeCP2 在 3D 染色体组织和细胞疾病表型拯救中的作用
  • 批准号:
    10339423
  • 财政年份:
    2020
  • 资助金额:
    $ 24.31万
  • 项目类别:

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