Molecular underpinnings of Prader-Willi syndrome
Molecular underpinnings of Prader-Willi syndrome
批准号:
10013261
负责人:
Gordon G Carmichael
金额:
$59.21万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-09-09 至 2024-06-30
关键词:
15qAllelesBehaviorChIP-seqChromatinChromatin StructureChromosomesComplexDiseaseEpigenetic ProcessExonsFailure to ThriveGene ExpressionGenesGeneticGoalsHyperphagiaIndividualInheritedKnock-outLearningMapsMediatingMessenger RNAMethylationMethyltransferaseModelingModificationMolecularMolecular ConformationMolecular TargetMorbid ObesityMuscle hypotoniaNeuronsNuclear Pore ComplexNucleic Acid Regulatory SequencesPharmacologyPlayPrader-Willi SyndromeProteinsRNARNA annealingRegulationRepressionRibosomal RNARoleSETDB1 geneSNRPNSiteSmall Nucleolar RNASomatic CellStructureTechniquesTherapeuticTissuesTranscriptUniparental DisomyWorkZinc Fingersdifferential expressionexperimental studygene repressionhistone methyltransferasehistone modificationhuman tissueimprintinduced pluripotent stem cellmRNA sequencingneurogeneticsrecruittool
中文摘要
摘要
Prader-Willi综合征(PWS)是一种神经遗传性疾病,
染色体15 q11-q13上的遗传基因。导致PWS的非典型缺失已经缩小
该疾病的关键遗传区域为包括SNORD 116在内的91 kb基因座。SNORD 116是
30个高度相似的C/D盒小核仁RNA(snoRNA)的簇。典型C/D盒
snoRNA退火并介导核糖体RNA的2 'O-甲基化(2'-OMe),然而,
SNORD 116拷贝与rRNA缺乏互补性。相反,他们被假设为修改
mRNA或lncRNA,但尚未鉴定出SNORD 116的直接靶标。因此他们的
神经元的功能尚不清楚。幸运的是,每个患有PWS的人都有一个完整的,
PWS关键区域的表观遗传抑制拷贝,包括SNORD 116,在其
母系等位基因我们最近发现,SNORD 116的母体拷贝可以被激活,
在PWS神经元中通过消耗ZNF 274(一种KRAB结构域锌指蛋白)。这不仅
提出了一种有趣的PWS治疗方法,但也提供了一种关键工具,
了解SNORD 116如何在神经元中调节。本提案的总体目标是
更好地了解PWS的分子基础。我们将确定染色质的状态
以及iPSC中活性和非活性15 q11-q13等位基因的长程染色质相互作用,
神经衍生物我们将研究SNORD 116如何通过ZNF 274耗尽而激活
和组蛋白甲基转移酶抑制影响染色质状态和长程相互作用。
最后,我们将确定SNORD 116的直接2 '-O-甲基化靶点,并确定如何
它们影响PWS相关的差异表达基因。
英文摘要
ABSTRACT
Prader-Willi syndrome (PWS) is a neurogenetic disorder caused by the loss of paternally
inherited genes on chromosome 15q11-q13. Atypical deletions that cause PWS have narrowed
the genetic region critical for the disorder to a 91kb locus including SNORD116. SNORD116 is
cluster of 30 highly similar C/D box small nucleolar RNAs (snoRNAs). Canonical C/D box
snoRNAs anneal to and mediate 2'O-methylation (2'-OMe) of ribosomal RNAs, however, the
SNORD116 copies lack complementarity to rRNAs. Instead they are hypothesized to modify
mRNAs or lncRNAs, but direct targets for SNORD116 have not been identified. Thus, their
function in neurons is not known. Fortunately, every individual with PWS has an intact, but
epigenetically repressed copy of the PWS critical region, including SNORD116, on their
maternal allele. We have recently shown that the maternal copy of SNORD116 can be activated
in PWS neurons by depleting ZNF274, a KRAB domain zinc finger protein. Not only does this
suggest an intriguing therapeutic approach to PWS, but also provides a critical tool to help
understand how SNORD116 is regulated in neurons. The overall goal of this proposal is to
better understand the molecular underpinnings of PWS. We will determine the chromatin states
and long-range chromatin interactions of active and inactive 15q11-q13 alleles in iPSCs and
neuronal derivatives. We will investigate how activation of SNORD116 via ZNF274 depletion
and histone methyltransferase inhibition impact the chromatin state and long-range interactions.
Finally, we will identify the direct 2'-O-methylation targets of SNORD116 and determine how
they influence PWS-related differentially expressed genes.
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会议论文
Molecular underpinnings of Prader-Willi syndrome
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批准号:10449980
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项目类别:
-
资助金额:$57.34万
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财政年份:2019
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负责人:Gordon G Carmichael
-
依托单位:
Molecular underpinnings of Prader-Willi syndrome
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批准号:10662498
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项目类别:
-
资助金额:$58.03万
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财政年份:2019
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负责人:Gordon G Carmichael
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依托单位:
Molecular underpinnings of Prader-Willi syndrome
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批准号:10199881
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项目类别:
-
资助金额:$58.03万
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财政年份:2019
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负责人:Gordon G Carmichael
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依托单位:
Nuclear-retained long noncoding RNAs
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批准号:9261581
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项目类别:
-
资助金额:$32.68万
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财政年份:2013
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负责人:Gordon G Carmichael
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依托单位:
Nuclear-retained long noncoding RNAs
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批准号:8917289
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项目类别:
-
资助金额:$31.87万
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财政年份:2013
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负责人:Gordon G Carmichael
-
依托单位:
Nuclear-retained long noncoding RNAs
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批准号:8579244
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项目类别:
-
资助金额:$32.63万
-
财政年份:2013
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负责人:Gordon G Carmichael
-
依托单位:
Nuclear-retained long noncoding RNAs
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批准号:8722581
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项目类别:
-
资助金额:$31.7万
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财政年份:2013
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负责人:Gordon G Carmichael
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依托单位:
The Fate of dsRNA in the Nucleus
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批准号:7002189
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项目类别:
-
资助金额:$24.78万
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财政年份:2003
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负责人:Gordon G Carmichael
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依托单位:
The Fate of dsRNA in the Nucleus
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批准号:6557232
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项目类别:
-
资助金额:$25.38万
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财政年份:2003
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负责人:Gordon G Carmichael
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依托单位:
The Fate of dsRNA in the Nucleus
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批准号:6835990
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项目类别:
-
资助金额:$25.38万
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财政年份:2003
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负责人:Gordon G Carmichael
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依托单位:
The Fate of dsRNA in the Nucleus
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批准号:6691697
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项目类别:
-
资助金额:$25.38万
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财政年份:2003
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负责人:Gordon G Carmichael
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依托单位:
PROCESSING AND FUNCTION OF POLYOMA RNA
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批准号:6362548
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项目类别:
-
资助金额:$30.52万
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财政年份:1987
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负责人:Gordon G Carmichael
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依托单位:
PROCESSING AND FUNCTION OF POLYOMA RNA
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批准号:6095264
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项目类别:
-
资助金额:$30.52万
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财政年份:1987
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负责人:Gordon G Carmichael
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依托单位:
PROCESSING AND FUNCTION OF POLYOMA RNA
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批准号:2091849
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项目类别:
-
资助金额:$21.7万
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财政年份:1987
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负责人:Gordon G Carmichael
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依托单位:
PROCESSING AND FUNCTION OF POLYOMA RNA
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批准号:2882346
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项目类别:
-
资助金额:$29.59万
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财政年份:1987
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负责人:Gordon G Carmichael
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依托单位:
Processing and Function of Polyoma RNA
-
批准号:7236046
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项目类别:
-
资助金额:$30.94万
-
财政年份:1987
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负责人:Gordon G Carmichael
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依托单位:
PROCESSING AND FUNCTION OF POLYOMA RNA
-
批准号:6512406
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项目类别:
-
资助金额:$30.52万
-
财政年份:1987
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负责人:Gordon G Carmichael
-
依托单位:
Processing and Function of Polyoma RNA
-
批准号:8900115
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项目类别:
-
资助金额:$31.93万
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财政年份:1987
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负责人:Gordon G Carmichael
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依托单位:
Processing and Function of Polyoma RNA
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批准号:8320881
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项目类别:
-
资助金额:$31.93万
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财政年份:1987
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负责人:Gordon G Carmichael
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依托单位:
PROCESSING AND FUNCTION OF POLYOMA RNA
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批准号:2376813
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项目类别:
-
资助金额:$26.89万
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财政年份:1987
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负责人:Gordon G Carmichael
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依托单位:
海外基金