表观遗传调控pre-mRNA的选择性剪接

选择性剪接是真核生物基因表达过程中的关键环节,是蛋白质多样性的主要来源,在生物的分化、发育及疾病的发生中扮演重要角色。传统的选择性剪接调控机制的研究多集中于RNA序列元件及与之相关的一些剪接因子,但近期的突破性研究指出表观遗传因素在选择性剪接的调控中发挥重要作用。DNA甲基化、染色质结构、组蛋白修饰相互影响并作用于pre-mRNA的选择性剪接,构成一个庞大、复杂的调控网络,表明表观遗传因素不仅决定着基因转录的起始,还影响其转录本剪接的结果。文章综述了近年来pre-mRNA选择性剪接的表观遗传调控的研究进展,探讨了DNA甲基化、染色质结构、组蛋白修饰在pre-mRNA选择性剪接中的可能作用,并展望了其对人类疾病研究所带来的深远影响。     

mRNA选择性剪接的分子机制

真核细胞mRNA前体经过剪接成为成熟的mRNA,而mRNA前体的选择性剪接极大地增加了蛋白质的多样性和基因表达的复杂程度,剪接位点的识别可以以跨越内含子的机制(内含子限定)或跨越外显子的机制(外显子限定)进行。选择性剪接有多种剪接形式：选择不同的剪接位点,选择不同的剪接末端,外显子的不同组合及内含子的剪接与否等。选择性剪接过程受到许多顺式元件和反式因子的调控,并与基本剪接过程紧密联系,剪接体中的一些剪接因子也参与了对选择性剪接的调控。选择性剪接也是1个伴随转录发生的过程,不同的启动子可调控产生不同的剪接产物。mRNA的选择性剪接机制多种多样,已发现RNA编辑和反式剪接也可参与选择性剪接过程。     

选择性剪接在植物逆境相关基因表达调控中的作用

文章介绍了选择性剪接在信号转导分子、转录因子、剪接因子和抗逆功能蛋白等4个层面对与植物逆境胁迫相关基因表达调控的影响,以及植物逆境诱导的选择性剪接机制的研究进展。     

选择性剪接与肿瘤靶向治疗

RNA剪接过程受到多种调节因子作用,以保证前体mRNA剪接的准确性。但是大量研究发现,在人类肿瘤中经常发生选择性剪接的异常或者来自特定癌症基因的剪接调控元件的突变。因此,RNA剪接调节剂作为一类新的癌蛋白和肿瘤抑制因子而逐渐受到关注,并有望通过调节参与致癌基因的RNA而达到治疗肿瘤的效果。改变RNA的异常剪接是治疗相关癌症的基础,这也为靶向治疗提供了更加丰富的靶点。本文综述了新发现的和预测的不同的剪接事件导致癌症的相关基因,并且对它们如何促成疾病的发病机制进行讨论。最后,我们总结了最新的针对可变剪接而发展的癌症诊断和治疗方法,包括使用小分子的剪接抑制剂来阻断剪接体或转录因子修饰酶,以调节特异性剪接导致的癌症。     

lncRNA选择性剪接调控的研究进展

长链非编码RNA (lncRNA)选择性剪接是指剪除未成熟lncRNA中的内含子,并将外显子连接起来生成成熟lncRNA的过程.在各类疾病发生和发展过程中,异常的选择性剪接起着重要作用. lncRNA选择性剪接直接参与膀胱癌、结直肠癌、肝癌、神经母细胞瘤等多种肿瘤的发病机制,且与胚胎发育、软骨毛发发育、多系统萎缩症等紧密相关.在此,我们对lncRNA选择性剪接的起因、调控机制以及对疾病影响的研究进展进行综述.此外,本文还介绍了两个与lncRNA选择性剪接相关的数据库(SpliceMap和LNCediting).     

选择性剪接调控蛋白PTB及同源蛋白的研究进展

选择性剪接(alternative splicing)是指一个前体m RNA通过选择不同的剪接位点组合产生多个可编码功能相似或相反的m RNA剪接异构体过程。多聚嘧啶结合蛋白(polypyrimidine tract-binding protein,PTB)作为一种剪接调控因子,它主要结合新生m RNA而抑制剪接发生。剪接调控的紊乱可导致肿瘤以及多种疾病的发生。本文详细阐述选择性剪接调控蛋白PTB及其同源蛋白的结构特征及选择性剪接与临床疾病的相关性的研究进展,从基因转录调控水平对疾病发生、发展以及预后有更深入的了解和认识,在许多疾病的研究中具有重要的应用前景。     

基因选择性剪接的生物信息学研究概况

基因选择性剪接现象是真核生物基本而又重要的调控机制。由于基因的选择性剪接在形成生物复杂性和多样性上具有极其重要的作用,同时选择性剪接与许多人类疾病也密切相关。因此,研究基因选择性剪接是一项十分重要的工作。生物信息学作为一门新兴的学科在研究基因选择性剪接上起关键的作用,尤其在研究基因表达调控机制、选择性剪接基因预测以及选择性剪接基因进化上。本文综述了这方面的最新研究进展,为更深入了解真核生物基因的表达调控机理提供依据。     

染色质结构与mRNA可变剪接

mRNA的可变剪接(alternative splicing)是一种由一个mRNA前体(pre-mRNA)通过不同的剪接方式产生多个mRNA变异体(variants)的RNA加工过程。在过去很长一段时间里,人们认为mRNA剪接过程是独立于转录过程的一个转录后RNA加工过程。然而,越来越多的实验证明mRNA剪接在很大程度上是与转录偶联发生的。因此,剪接调控会受到与转录相关因素的调控。本文将对染色质与mRNA剪接调控的相关性和染色质结构调控可变剪接的分子机制进行阐述。     

植物基因选择性剪接:断舍离合,达权知变

选择性剪接是基因转录后的mRNA通过不同的剪接方式产生多样性成熟转录本的过程,是真核生物细胞中一种重要的转录后调控方式。植物基因也常通过这种断舍离合的方式产生一专多能的转录本,达到调节多种生命活动的目的。相较于动物,植物中该领域的研究起步较晚,但近年来也取得了长足的进步。该文综述了植物基因选择性剪接的生物学意义、剪接方式和机制、研究方法以及在生长发育与环境胁迫适应性调节中的作用,并展望了未来的研究方向。     

选择性剪接调控机制的研究进展

选择性剪接是真核生物控制基因表达的一种重要机制,生物体通过这种机制使有限的基因得以表达大量复杂的蛋白质。最近的研究表明,它的调控机制涉及一系列正性和负性调控信号分子,本文综述调控选择性剪接发生的重要剪接因子及其信号机制。     

The coded functions of noncoding RNAs for gene regulation

For eukaryotes, fine tuning of gene expression is necessary to coordinate complex genetic information. Recent studies have shown that noncoding RNAs (ncRNAs) play central roles in this process. For example, ncRNAs participate in multiple diverse functions such as mRNA degradation, epigenetic regulation and alternative splicing. The findings regarding this new player in gene regulation suggest that the mechanism of gene regulation is much more complicated and subtle than previously thought. In this review, new findings concerning the role of ncRNAs in gene regulation are discussed.     

Regulation of protein diversity by alternative pre-mRNA splicing with specific focus on chondrogenesis

Analysis of the human genome has dramatically demonstrated that the majority of protein diversity is generated by alternative splicing of pre-mRNA. This powerful and versatile mechanism controls the synthesis of functionally different protein isoforms that may be required during specific stages of development from a single gene. Consequently, ubiquitous and/or tissue-specific RNA splicing factors that regulate this splicing mechanism provide the basis for defining phenotypic characteristics of cells during differentiation. In this review, we will introduce the basic mechanisms of pre-mRNA alternative splicing, describe how this process is regulated by specific RNA splicing factors, and relate this to various systems of cell differentiation. Chondrogenesis, a well-defined differentiation pathway necessary for skeletogenesis, will be discussed in detail, with focus on some of the alternatively-spliced proteins known to be expressed during cartilage development. We propose a heuristic view that, ultimately, it is the regulation of these RNA splicing factors that determines the differentiation status of a cell. Studying regulation at the level of pre-mRNA alternative splicing will provide invaluable insights into how many developmental mechanisms are controlled, thus enabling us to manipulate a system to select for a specific differentiation pathway.     

表观遗传因素在RNA剪接过程中的作用

RNA剪接是真核生物基因表达过程中的重要环节,增加了蛋白质的多样性和基因表达的可调节性. 日益增多的研究表明,RNA剪接并不是独立的生物过程.RNA Ⅱ型聚合酶(RNA polymerase-Ⅱ, RNA Pol Ⅱ)、核小体定位和组蛋白修饰等因素都与RNA剪接过程密切相关.阐明RNA Pol Ⅱ、核小体定位和组蛋白修饰等因素在RNA剪接过程中的作用,将为剪接位点的准确识别和剪接调控机制的研究提供新思路.本文综述了RNA Pol Ⅱ、核小体定位和组蛋白修饰等因素对RNA剪接的影响以及它们在RNA剪接过程中的调控作用.     

综述:转录后基因调控异常与老年性痴呆

转录后基因调控异常与阿尔茨海默病(Alzheimer's disease,AD)发生发展的关系研究越来越受到重视．本文重点论述了tau基因(MAPT)发生可变剪接异常与AD发生的关系,以及参与转录后调控的RNA结合蛋白和非编码RNA在AD发生发展中的作用．     

Efficient in vivo manipulation of alternative pre-mRNA splicing events using antisense morpholinos in mice

Mammalian pre-mRNA alternative splicing mechanisms are typically studied using artificial minigenes in cultured cells, conditions that may not accurately reflect the physiological context of either the pre-mRNA or the splicing machinery. Here, we describe a strategy to investigate splicing of normal endogenous full-length pre-mRNAs under physiological conditions in live mice. This approach employs antisense vivo-morpholinos (vMOs) to mask cis-regulatory sequences or to disrupt splicing factor expression, allowing functional evaluation of splicing regulation in vivo. We applied this strategy to gain mechanistic insight into alternative splicing events involving exons 2 and 16 (E2 and E16) that control the structure and function of cytoskeletal protein 4.1R. In several mouse tissues, inclusion of E16 was substantially inhibited by interfering with a splicing enhancer mechanism using a target protector morpholino that blocked Fox2-dependent splicing enhancers in intron 16 or a splice-blocking morpholino that disrupted Fox2 expression directly. For E2, alternative 3'-splice site choice is coordinated with upstream promoter use across a long 5'-intron such that E1A splices almost exclusively to the distal acceptor (E2dis). vMOs were used to test the in vivo relevance of a deep intron element previously proposed to determine use of E2dis via a two-step intrasplicing model. Two independent vMOs designed against this intronic regulatory element inhibited intrasplicing, robustly switching E1A splicing to the proximal acceptor (E2prox). This finding strongly supports the in vivo physiological relevance of intrasplicing. vMOs represent a powerful tool for alternative splicing studies in vivo and may facilitate exploration of alternative splicing networks in vivo.     

Epigenetics in alternative pre-mRNA splicing

Alternative splicing plays critical roles in differentiation, development, and disease and is a major source for protein diversity in higher eukaryotes. Analysis of alternative splicing regulation has traditionally focused on RNA sequence elements and their associated splicing factors, but recent provocative studies point to a key function of chromatin structure and histone modifications in alternative splicing regulation. These insights suggest that epigenetic regulation determines not only what parts of the genome are expressed but also how they are spliced.     

Signals, pathways and splicing regulation

Alternative splicing of messenger RNA precursors is an extraordinary source of protein diversity and the regulation of this process is crucial for diverse cellular functions in both physiological and pathological situations. For many years, several signaling pathways have been implicated in alternative splicing regulation. Recent work has begun to unravel the molecular mechanisms by which extracellular stimuli activate signaling cascades that modulate the activity of the splicing machinery and therefore the splicing pattern of many different target messenger RNA precursors. These experiments are revealing unexpected aspects of the mechanism that control splicing and the consequences of the regulated splicing events. We summarize here the current knowledge about signal-induced alternative splicing regulation of Slo, NR1, CD44, CD45 and fibronectin genes, and also discuss the importance of some of these events in determination of cellular fate. Furthermore, we highlight the relevance of signal-induced changes in phosphorylation state and subcellular distribution of splicing factors as a way of regulating the splicing process. Lastly, we explore new and unexpected findings about regulated splicing in anucleated cells.