TRANSCRIPTION AND RNA BINDING IN FRAGILE X SYNDROME
脆性 X 综合征中的转录和 RNA 结合
基本信息
- 批准号:6241403
- 负责人:
- 金额:$ 17.11万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1997
- 资助国家:美国
- 起止时间:1997-09-10 至 1998-07-31
- 项目状态:已结题
- 来源:
- 关键词:DNA methylation RNA binding protein behavioral /social science research tag behavioral genetics cell line crosslink disease /disorder etiology fragile X syndromes gene induction /repression gene mutation genetic mapping genetic promoter element genetic regulatory element genetic transcription genetically modified animals immunoprecipitation laboratory rat nuclear runoff assay nucleic acid repetitive sequence sex linked trait site directed mutagenesis transcription factor transfection
项目摘要
Loss of function of the FMR1 gene in humans leads to the Fragile X
mental Retardation syndrome. FMR1 encodes an RNA-binding protein of
unknown function. Most mutations in the gene result in expansion of a
polymorphic trinucleotide repeat to sizes greater than 1 kilobase.
Expansion of this repeat, which resides in the 5'-untranslated portion
of FMR1, is associated with hypermethylation of the locus and a loss in
steady-state levels of mRNA. The biochemical and molecular basis for
this inactivation is, however, unknown including the specific DNA
elements whose methylation results in transcriptional silencing of the
gene. Using nuclear-runon assays, we will test directly whether the
rate of initiation of transcription is compromised in alleles of varying
repeat number and methylation state. We will also test an alternative
hypothesis that transcription through the expanded poly (CGG) reduces
the output of FMR1 transcript due to a blockage of transcript
elongation, as seen for other human DNA sequences that deviate from the
canonical B DNA structure. In such cases, transcription is rendered
elongation factor-dependent.
Other mechanisms of loss of FMR1 gene product function have been
described. One allele of FMR1 containing a point mutation encodes an
RNA binding-defective protein. The 3- dimensional surface of FMR
protein that contacts RNA is not known. In this project we will
investigate the basic mechanisms of disease causation due to FMR1
mutation at the level of FMR1 transcription initiation, elongation, and
RNA-binding by the FMR protein itself. The specific aims are:
1) to define the cis-acting sequences that serve as targets for
methylation-mediated inactivation of promoter function,
2) to measure transcription rate changes as a function of the
methylation state of specific FMR1 promoter elements and the CGG-repeat
size,
3) to assess transcription through CGG repeats as a function of the
extent of triplet expansion in vivo and in vitro,
4) to map the residues of FMRP that are in close contact with RNA using
photo cross-linking of purified FMRP and modified RNA. This will
complement high resolution structural studies of the FMR gene product.
Mutants in the RNA-contacting surface of the FMR protein will be tested
for function in vitro and in vivo.
人类FMR 1基因功能丧失导致脆性X染色体
智力迟钝综合症 FMR 1编码一种RNA结合蛋白,
未知函数 基因中的大多数突变会导致
多态性三核苷酸重复的大小大于1个碱基。
此重复序列的扩增,其位于5 '-未翻译部分
FMR 1基因的突变与该基因座的高甲基化和FMR 1基因的缺失有关。
mRNA的稳态水平。 生物化学和分子基础
然而,这种失活是未知的,包括特定的DNA
其甲基化导致转录沉默的元件,
基因 使用核试验,我们将直接测试是否
转录起始速率在不同的等位基因中受到损害,
重复数和甲基化状态。 我们还将测试一种替代方案
假设通过扩展的多聚(CGG)的转录减少了
由于转录物阻断而导致FMR 1转录物输出
延伸,如对于偏离所述延伸的其他人类DNA序列所见。
典型的B DNA结构。 在这种情况下,
延伸因子依赖性。
FMR 1基因产物功能丧失的其他机制已被发现。
介绍了 含有点突变的FMR 1的一个等位基因编码
RNA结合缺陷蛋白。 FMR的三维表面
与RNA接触的蛋白质未知。 在这个项目中,我们将
探讨FMR 1致病的基本机制
在FMR 1转录起始、延伸和
FMR蛋白自身的RNA结合。 具体目标是:
1)来定义作为靶点的顺式作用序列,
甲基化介导的启动子功能失活,
2)为了测量转录速率变化,
特异性FMR 1启动子元件和CGG重复序列的甲基化状态
尺寸,
3)为了评估通过CGG重复的转录,
体内和体外三联体扩增的程度,
4)为了绘制与RNA密切接触的FMRP残基,
纯化的FMRP和修饰的RNA的光交联。 这将
补充FMR基因产物的高分辨率结构研究。
将测试FMR蛋白质的RNA接触表面中的突变体
for function功能in vitro体外and in vivo体内.
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Daniel Reines其他文献
Daniel Reines的其他文献
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{{ truncateString('Daniel Reines', 18)}}的其他基金
Biochemical & Genetic Analysis of Low Complexity Domains in RNA-binding protein biology
生化
- 批准号:
9335978 - 财政年份:2016
- 资助金额:
$ 17.11万 - 项目类别:
Biochemical & Genetic Analysis of Low Complexity Domains in RNA-binding protein biology
生化
- 批准号:
9158657 - 财政年份:2016
- 资助金额:
$ 17.11万 - 项目类别:
RNA Polymerase II Elongation Complex:Structure-Function
RNA 聚合酶 II 延伸复合物:结构-功能
- 批准号:
7907163 - 财政年份:2009
- 资助金额:
$ 17.11万 - 项目类别:
TRANSCRIPTION AND RNA BINDING IN FRAGILE X SYNDROME
脆性 X 综合征中的转录和 RNA 结合
- 批准号:
6613926 - 财政年份:2002
- 资助金额:
$ 17.11万 - 项目类别:
TRANSCRIPTION AND RNA BINDING IN FRAGILE X SYNDROME
脆性 X 综合征中的转录和 RNA 结合
- 批准号:
6202115 - 财政年份:1999
- 资助金额:
$ 17.11万 - 项目类别:
TRANSCRIPTION AND RNA BINDING IN FRAGILE X SYNDROME
脆性 X 综合征中的转录和 RNA 结合
- 批准号:
6108901 - 财政年份:1998
- 资助金额:
$ 17.11万 - 项目类别:
TRANSCRIPTION AND RNA BINDING IN FRAGILE X SYNDROME
脆性 X 综合征中的转录和 RNA 结合
- 批准号:
6501527 - 财政年份:1997
- 资助金额:
$ 17.11万 - 项目类别:
RNA POLYMERASE II ELONGATION COMPLEX STRUCTURE/FUNCTION
RNA 聚合酶 II 延伸复合物结构/功能
- 批准号:
2444797 - 财政年份:1991
- 资助金额:
$ 17.11万 - 项目类别:
RNA POLYMERASE II ELONGATION COMPLEX--STRUCTURE/FUNCTION
RNA 聚合酶 II 延伸复合物——结构/功能
- 批准号:
6519456 - 财政年份:1991
- 资助金额:
$ 17.11万 - 项目类别:
RNA polymerase II Elongation Complex: Structure and Function
RNA 聚合酶 II 延伸复合物:结构和功能
- 批准号:
8527791 - 财政年份:1991
- 资助金额:
$ 17.11万 - 项目类别:
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