CTCF-dependent mechanisms of ATRX in neuronal differentiation

ATRX 在神经元分化中的 CTCF 依赖性机制

基本信息

  • 批准号:
    10625522
  • 负责人:
  • 金额:
    $ 53.06万
  • 依托单位:
  • 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:
    2022-07-01 至 2027-06-30
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY ATRX is an epigenetic factor that is mutated in ATRX syndrome. ATRX is required for the maintenance of multipotent neuroprogenitor cells (NPCs), particularly as these cells initiate differentiation programs in the brain. Mutations that cause ATRX syndrome cluster within two domains: the ATRX PHD finger domain, and the helicase domain. These mediate interactions with histones, and remodel chromatin, respectively. Interestingly, mutations in the PHD finger are associated with severe intellectual disability and psychomotor impairment, while mutations in the helicase domain often manifest with milder neurodevelopmental delays but more severe genital abnormalities13. The basis for this genotype-phenotype correlation has never been investigated. ATRX has well- established roles in molecular processes that are crucial for normal brain development including histone variant H3.3 deposition and Polycomb repressive complex 2 targeting for epigenetic silencing. It also has a poorly understood role in regulating CTCF, a critical genome architectural protein that is essential for development. Our preliminary data indicate PHD finger and helicase mutations of ATRX differentially regulate CTCF localization and may underlie genotype-phenotype correlations. Our preliminary data has uncovered a genome-wide role for ATRX in CTCF localization. We found that ATRX knock down (KD) in mouse embryonic stem cells (mESCs) results in CTCF accumulation at many genomic sites, including both imprinted and non-imprinted loci. We also discovered that ATRX interacts with ADNP and DNMT3L, both of which can prevent CTCF binding. Using CRISPR/Cas9, we have generated isogenic ESCs where the endogenous Atrx allele has been replaced by point mutants found in ATRX syndrome patients. We show that mutations in the PHD finger cause significant impairment of NPC differentiation, while mutations in the helicase domain cause more subtle differentiation delays. Our preliminary findings and novel reagents uniquely position us to interrogate the consequence of ATRX mutations, both for genome organization through CTCF, and for the ability of ESCs to differentiate into NPCs. Based on our preliminary data, we propose to test the hypothesis that distinct ATRX domains regulate specific chromatin processes that impinge to different extents on the function of CTCF. In Aim 1, we will investigate the consequence of ATRX syndrome mutations to gene expression and genome organization during neuronal differentiation. In Aim 2, we will decipher the mechanisms by which ATRX regulates CTCF localization.
项目总结 ATRX是一种表观遗传因子,在ATRX综合征中发生突变。需要ATRX来维护 多能神经前体细胞,特别是当这些细胞在大脑中启动分化程序时。 在两个区域内导致ATRX综合征聚集性的突变:ATRX PhD指状域和 解旋酶结构域。它们分别调节与组蛋白的相互作用和重塑染色质。有趣的是, PhD手指的突变与严重的智力残疾和精神运动障碍有关,而 解旋酶区域的突变通常表现为较轻微的神经发育延迟但较严重的生殖器发育迟缓 反常行为13.这种基因型-表型相关性的基础从未被研究过。ATRX有很好的- 在包括组蛋白变体在内的对正常大脑发育至关重要的分子过程中已确立的角色 H3.3沉积和多梳抑制复合体2靶向于表观遗传沉默。它也有一个糟糕的 了解在调节CTCF中的作用,CTCF是一种对发育至关重要的关键基因组结构蛋白。我们的 初步数据表明,PHD手指和ATRX解旋酶突变对CTCF定位有不同的调节作用 并且可能是基因-表型相关性的基础。我们的初步数据揭示了一种全基因组的作用 CTCF本地化中的ATRX。我们在小鼠胚胎干细胞(MESCs)中发现ATRX基因敲除(KD) 导致CTCF在许多基因组位置积累,包括印迹和非印迹基因座。我们也 发现ATRX与ADNP和DNMT3L相互作用,这两种物质都可以阻止CTCF结合。vbl.使用 CRISPR/Cas9,我们已经产生了等基因ESCs,其中内源性ATRX等位基因已经被POINT取代 在ATRX综合征患者中发现突变。我们发现,PHD手指的突变会导致显著的 鼻咽癌分化的障碍,而解旋酶区域的突变导致更微妙的分化 耽搁了。我们的初步发现和新的试剂使我们能够独一无二地询问ATRX的后果 突变,包括通过CTCF的基因组组织,以及ESCs分化为NPC的能力。 基于我们的初步数据,我们建议检验不同的ATRX结构域调节特定基因的假设 染色质过程对CTCF功能有不同程度的影响。在目标1中,我们将调查 ATRX综合征突变对神经细胞基因表达和基因组结构的影响 差异化。在目标2中,我们将破译ATRX调节CTCF本地化的机制。

项目成果

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Kavitha Sarma其他文献

Kavitha Sarma的其他文献

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{{ truncateString('Kavitha Sarma', 18)}}的其他基金

ADNP mechanisms in R-loop regulation during differentiation
ADNP 在分化过程中 R 环调节的机制
  • 批准号:
    10444141
  • 财政年份:
    2022
  • 资助金额:
    $ 53.06万
  • 项目类别:
Developing a genomic toolkit to identify RNAs within non-canonical DNA structures
开发基因组工具包来识别非规范 DNA 结构中的 RNA
  • 批准号:
    10708851
  • 财政年份:
    2022
  • 资助金额:
    $ 53.06万
  • 项目类别:
Developing a genomic toolkit to identify RNAs within non-canonical DNA structures
开发基因组工具包来识别非规范 DNA 结构中的 RNA
  • 批准号:
    10506451
  • 财政年份:
    2022
  • 资助金额:
    $ 53.06万
  • 项目类别:
Molecular and neurodevelopmental consequences of ADNP mutation
ADNP 突变的分子和神经发育后果
  • 批准号:
    10372679
  • 财政年份:
    2021
  • 资助金额:
    $ 53.06万
  • 项目类别:
Molecular and neurodevelopmental consequences of ADNP mutation
ADNP 突变的分子和神经发育后果
  • 批准号:
    10491348
  • 财政年份:
    2021
  • 资助金额:
    $ 53.06万
  • 项目类别:
Epigenetic regulation through the formation and resolution of R loops
通过 R 环的形成和解析进行表观遗传调控
  • 批准号:
    9350668
  • 财政年份:
    2017
  • 资助金额:
    $ 53.06万
  • 项目类别:
Deciphering the Role of MacroH2A in Non-coding RNA Mediated Silencing
解读 MacroH2A 在非编码 RNA 介导的沉默中的作用
  • 批准号:
    8044167
  • 财政年份:
    2010
  • 资助金额:
    $ 53.06万
  • 项目类别:
Deciphering the Role of MacroH2A in Non-coding RNA Mediated Silencing
解读 MacroH2A 在非编码 RNA 介导的沉默中的作用
  • 批准号:
    7806710
  • 财政年份:
    2010
  • 资助金额:
    $ 53.06万
  • 项目类别:

相似海外基金

Molecular pathological mechanisms of the brain development disorder using the chromatin-remodeling molecule ATRX gene knockout mouse
染色质重塑分子ATRX基因敲除小鼠脑发育障碍的分子病理机制
  • 批准号:
    23300147
  • 财政年份:
    2011
  • 资助金额:
    $ 53.06万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Functional analysis of the Zn finger domain encoded by the ATRX gene whose mutations result in X-linked alpha thalassemia mental retardation(ATR-X) syndrome
ATRX基因编码的锌指结构域的功能分析,其突变导致X连锁α地中海贫血精神发育迟滞(ATR-X)综合征
  • 批准号:
    18570170
  • 财政年份:
    2006
  • 资助金额:
    $ 53.06万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
A Y CHROMOSOME MODEL FOR THE SEX DETERMINING FUNCTION OF THE HUMAN ATRX GENE
人类 ATRX 基因性别决定功能的 Y 染色体模型
  • 批准号:
    nhmrc : 148630
  • 财政年份:
    2001
  • 资助金额:
    $ 53.06万
  • 项目类别:
    NHMRC Project Grants
Investigation of the role of the ATRX gene in normal mammalian development
ATRX 基因在正常哺乳动物发育中的作用研究
  • 批准号:
    nhmrc : 987013
  • 财政年份:
    1998
  • 资助金额:
    $ 53.06万
  • 项目类别:
    Early Career Fellowships
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