Comprehensive analysis of the FMR1 locus transcriptional landscape

FMR1位点转录景观的综合分析

• 批准号: 8258038
• 负责人: Claes Robert Wahlestedt
• 金额: $ 29.38万
• 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/8258038
• 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）：脆弱的X综合征（FXS）是遗传性智障的最常见形式（Oostra，1996）。它是由FMR1的5'UTR中的CGG扩展引起的，这导致缺乏脆弱的X智力低下蛋白（FMRP）。然而，脆弱X患者的纵向临床观察表明，FXS认知，行为和形态学症状的严重程度高度可变。因此，我们搜索了从FMR1基因座表达的新功能转录本，并鉴定出FMR4，这是一种长的非编码RNA，具有强生物（抗凋亡）活性。另一个小组确定了源自FMR1基因座ASFMR1的第二个长的非编码转录本，但目前尚不清楚它是否具有任何生物学活性。有趣的是，与FMR1相似的FMR4和ASFMR1在脆弱的X患者中都沉默，并在久经考前的载体中上调。表达分析表明，FMR4和ASFMR1在各种人类的成年和胚胎组织中表达。原位杂交研究表明，FMR4位于原子核上，表明FMR4具有核的作用方式。由于FMR4具有明显的生物学活性，并且在FXS中被沉默，因此FMR4是用于参与FXS和相关疾病的新候选基因。如果FMR4，ASFMR1的活性和未表征的FMR1衍生的非编码RNA与FXS中FMR1的表达和沉默有关，则尚未解决。以前已经证明，非编码RNA可以用作染色质修饰复合物的界面，而短的非编码RNA，例如microRNA，可以通过与哺乳动物细胞中与启动子相关的RNA相互作用指导表观遗传修饰来诱导或抑制基因的转录。因此，探索FMR1启动子是否存在此类调节以及是否可以操纵这种调节以恢复脆弱X患者的FMR1表达。 公共卫生相关性：智力障碍定义为对童年时期基本运动和语言技能的持续缓慢学习，成年后的智力低下。近613,000名6至21岁的美国儿童具有一定程度的智力障碍，需要在学校接受特殊教育（美国教育部的第24届年度报告，2002年）。脆弱的X综合征是智力低下的主要遗传原因。它影响了1/4,000名男孩和1/6,000名女孩。我们的初步研究（发现在脆弱的X综合征中被沉默的新基因的发现）以及该应用的拟议目的将为理解脆弱的X综合征和心理健康的理解提供重要的一步。 FMR1基因座中的新成绩单（FMR4）和其他潜在转录本可能与脆弱的X综合征和/或相关疾病具有临床相关性。