Comprehensive analysis of the FMR1 locus transcriptional landscape

FMR1位点转录景观的综合分析

• 批准号: 8066450
• 负责人: Claes Robert Wahlestedt
• 金额: $ 15.17万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 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 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8066450
• 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; Health; 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. PUBLIC HEALTH RELEVANCE: Mental retardation is defined as a persistent slow learning of basic motor and language skills during childhood, and a significantly below-normal intellectual capacity as an adult. Nearly 613,000 American children ages 6 to 21 have some level of mental retardation and need special education in school (Twenty-fourth Annual Report to Congress, U.S. Department of Education, 2002). Fragile X syndrome is the leading genetic cause of mental retardation; it affects 1/4,000 boys and 1/6,000 girls. Our preliminary studies (discovery of a new gene that is silenced in fragile X syndrome) and the proposed aims of this application will provide a significant step toward the understanding of fragile X syndrome and mental health in general. This new transcript (FMR4) and other potential transcripts in the FMR1 locus may have clinical relevance to fragile X syndrome and/or related disorders.

描述（由申请人提供）：脆性X综合征（Fragile X syndrome，简称FXS）是遗传性智力低下最常见的一种形式（Oostra, 1996）。它是由FMR1的5' UTR中的CGG扩增引起的，这导致脆性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、行为和形态学症状的严重程度是高度可变的。因此，我们寻找从FMR1位点表达的新的功能转录本，并鉴定出FMR4，这是一种具有强生物学（抗凋亡）活性的长链非编码RNA。另一组发现了来自FMR1位点的第二个长非编码转录本ASFMR1，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患者中沉默，而在突变前携带者中上调。表达分析表明，FMR4和ASFMR1在成人和胚胎组织中广泛表达。原位杂交研究表明，FMR4定位于细胞核，表明FMR4发挥核模式的作用。由于FMR4具有明显的生物活性，并且在FXS中沉默，因此FMR4是参与FXS及相关疾病的新候选基因。目前尚不清楚FMR4、ASFMR1和尚未鉴定的FMR1衍生的非编码rna的活性是否与FMR1在FXS中的表达和沉默有关。先前已经证明，非编码rna可以作为染色质修饰复合物的接口，并且短的非编码rna，例如microRNAs，可以通过与哺乳动物细胞中的启动子相关rna相互作用来指导表观遗传修饰，从而诱导或抑制基因的转录。因此，探索FMR1启动子是否存在这种调控，以及是否可以操纵这种调控来恢复脆性X患者的FMR1表达，是我们感兴趣的。