Comprehensive analysis of the FMR1 locus transcriptional landscape

FMR1位点转录景观的综合分析

• 批准号: 8607595
• 负责人: Claes Robert Wahlestedt
• 金额: $ 37.87万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-26 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8607595
• 关键词: 5' Untranslated Regions; Active Sites; Adult; Affect; Age; American; Annual Reports; Apoptotic; Autistic Disorder; Behavioral; Biological; Candidate Disease Gene; Cell Nucleus; Cells; Child; Childhood; Chromatin; Chromatin Structure; Clinical; Code; Cognitive; Complex; Congresses; Data; Disease; Education; Epigenetic Process; FMR1; FMR1 Gene; Fragile X Mental Retardation Protein; Fragile X Syndrome; Functional RNA; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genome; Genomics; Human; Human Cell Line; In Situ Hybridization; Inherited; Laboratories; Language; Learning; Link; Mammalian Cell; Mental Health; Mental Retardation; MicroRNAs; Modification; Motor; Mouse Cell Line; Mus; Names; Nuclear; Orthologous Gene; Patients; Phenotype; Play; Premature Ovarian Failure; Property; Proteins; Regulation; Resolution; Schools; Severities; Special Education; Structure-Activity Relationship; Symptoms; Time; Transcript; Tremor/Ataxia Syndrome; autism spectrum disorder; boys; clinically relevant; embryo tissue; falls; gene function; genome wide association study; genome-wide; girls; human disease; interest; mRNA Expression; mammalian genome; mutation carrier; novel; novel strategies; promoter; protein expression; public health relevance; skills

DESCRIPTION (provided by applicant): Fragile X syndrome (FXS) is the most common form of inherited mental retardation (Oostra, 1996). It is caused by a CGG expansion in the 5' UTR of FMR1, which leads to the absence of the fragile X mental retardation protein (FMRP). However, longitudinal clinical observations of fragile X patients have shown that the severity of the cognitive, behavioral and morphological symptoms of FXS is highly variable. Therefore we searched for novel functional transcripts expressed from the FMR1 locus and identified FMR4, a long non-coding RNA with a strong biological (anti-apoptotic) activity. Another group identified a second long non-coding transcript originating from the FMR1 locus, ASFMR1, but it is yet unclear if it has any biological activity. Interestingly, both FMR4 and ASFMR1, similar to FMR1, are silenced in fragile X patients and up-regulated in pre-mutation carriers. Expression analyses have shown that FMR4 and ASFMR1 are expressed in a wide range of human adult and embryonic tissues. In situ hybridization studies demonstrated that FMR4 is localized to the nucleus suggesting that FMR4 exerts a nuclear mode of action. Since FMR4 has pronounced biological activity and is silenced in FXS, FMR4 is a new candidate gene for involvement in FXS and related disorders. It is unresolved if the activity of FMR4, ASFMR1, and yet uncharacterized FMR1-derived non-coding RNAs is linked to expression and silencing of FMR1 in FXS. It has been previously demonstrated that non-coding RNAs can serve as an interface for chromatin- modifying complexes and that short non-coding RNAs, e.g. microRNAs, can induce or repress the transcription of genes by directing epigenetic modifications via interaction with promoter-associated RNAs in mammalian cells. It is therefore of interest to explore whether such regulation exists at the FMR1 promoter and whether such regulation can be manipulated to restore FMR1 expression in fragile X patients.

描述（由申请人提供）：脆性 X 综合征（FXS）是遗传性智力低下的最常见形式（Oostra，1996）。它是由 FMR1 5' UTR 中的 CGG 扩展引起的，导致脆性 X 智力迟钝蛋白 (FMRP) 的缺失。然而，对脆性 X 患者的纵向临床观察表明，FXS 的认知、行为和形态症状的严重程度差异很大。因此，我们寻找从 FMR1 位点表达的新功能转录本，并鉴定出 FMR4，一种具有强生物（抗凋亡）活性的长非编码 RNA。另一个研究小组鉴定了源自 FMR1 位点 ASFMR1 的第二个长非编码转录本，但尚不清楚它是否具有任何生物活性。有趣的是，与 FMR1 类似，FMR4 和 ASFMR1 在脆性 X 患者中均被沉默，而在突变前携带者中表达上调。表达分析表明，FMR4 和 ASFMR1 在多种人类成人和胚胎组织中表达。原位杂交研究表明 FMR4 定位于细胞核，表明 FMR4 发挥核作用模式。由于 FMR4 具有显着的生物活性并且在 FXS 中被沉默，因此 FMR4 是参与 FXS 和相关疾病的新候选基因。 FMR4、ASFMR1 和尚未表征的 FMR1 衍生非编码 RNA 的活性是否与 FXS 中 FMR1 的表达和沉默有关尚待解决。先前已经证明，非编码 RNA 可以作为染色质修饰复合物的界面，并且短的非编码 RNA，例如microRNA 可以通过与哺乳动物细胞中启动子相关的 RNA 相互作用来指导表观遗传修饰，从而诱导或抑制基因转录。因此，探索 FMR1 启动子处是否存在这种调节以及是否可以操纵这种调节来恢复脆性 X 患者中的 FMR1 表达是很有意义的。

项目成果

Reprogramming of mPFC transcriptome and function in alcohol dependence.

• DOI: 10.1111/gbb.12344
• 发表时间: 2017-01
• 期刊: Genes, brain, and behavior
• 作者: Heilig M;Barbier E;Johnstone AL;Tapocik J;Meinhardt MW;Pfarr S;Wahlestedt C;Sommer WH
• 通讯作者: Sommer WH

Comprehensive analysis of the transcriptional landscape of the human FMR1 gene reveals two new long noncoding RNAs differentially expressed in Fragile X syndrome and Fragile X-associated tremor/ataxia syndrome.

• DOI: 10.1007/s00439-013-1356-6
• 发表时间: 2014-01
• 期刊: HUMAN GENETICS
• 影响因子: 5.3
• 作者: Pastori, Chiara;Peschansky, Veronica J.;Barbouth, Deborah;Mehta, Arpit;Silva, Jose P.;Wahlestedt, Claes
• 通讯作者: Wahlestedt, Claes