Investigating microRNA:target gene interactions in myogenesis

研究 microRNA：肌生成中靶基因的相互作用

• 批准号: BB/H019979/1
• 负责人: Andrea Munsterberg
• 金额: $ 64.95万
• 依托单位: University of East Anglia
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FH019979%2F1
• 关键词: Investigating; microRNA; target; gene; interactions

Multi-cellular organisms contain many distinct cell types with very specialized functions. For example, we need skeletal muscle to be able to move while our skin prevents dehydration and protects us from injury and infections. Amazingly all these different cells arise from a single cell, the fertilized egg. The development of an embryo begins when the egg starts dividing to give rise to many cells. Different cells are specified during embryonic development - they are essentially told what to do and what to become by molecular signals that act in the early embryo. These signals often cause specific genes to be switched 'on' or 'off'. If a gene is 'on' it is expressed which means that it is actively transcribed from the DNA in the nucleus of the cell. During the process of transcription, DNA is copied into RNA. These RNA transcripts typically encode proteins and RNA is translated into proteins by a complex cellular machinery. Proteins are the 'movers and shakers' in a cell, they define a cell and they have specific jobs to do. For example, the contraction of skeletal muscle is mediated by fast and slow contractile fibres (made up of proteins). Muscle is a very plastic tissue and depending on whether you train to be a 100 m sprinter or a marathon runner different types of muscle proteins will be expressed. Muscle also has the ability to repair itself (to regenerate) for example after wearing a cast muscle is lost, but it builds up again quickly when the muscle is used again. We are interested in the molecules that control the development of muscle in an embryo, it is known that some of these (including some that we previously discovered, called 'Wnt') are also used during muscle regeneration. In particular we study a class of RNA molecules, which are not translated to make proteins. Here the RNA molecule itself has an important functions. These non-coding RNAs were discovered recently and because they are very small, they were called microRNAs (miRs). They have been found in plants and animals, which means, that they are part of the most basic machinery of life with a very important and fundamental job to do in all cells. This turned out to be the case and in fact microRNAs control whether or not other coding RNAs are translated into protein. A lot of research is being done, to help understand how this is happening and to uncover what type of cellular processes are controlled in this fashion. Our research investigates how cells become different from one another in a developing vertebrate embryo. In particular, we study the genes and molecules that control the decision of a cell to differentiate into skeletal muscle from a multi-potent precursor, as opposed to into bone for example. We recently discovered that two of these new microRNAs (and there are currently more than 400 microRNAs known) are only present in those cells in the embryo, that will go on to make skeletal muscle and we want to understand what the role of these microRNAs is. We have already figured out how the production of the microRNA itself is being switched 'on' or 'off', and we have identified some of the genes controlled by the microRNAs (the 'targets'). Ideally we want to identify all the target genes and we also need to understand how they in turn affect skeletal muscle. Overall we will learn how an embryo makes normal, healthy, working muscle and this will in the long-term benefit people who suffer from various muscle degenerative diseases or age related muscle-loss.

多细胞生物体包含许多具有非常专门功能的不同细胞类型。例如，我们需要骨骼肌能够移动，而我们的皮肤可以防止脱水，保护我们免受伤害和感染。令人惊讶的是，所有这些不同的细胞都来自一个细胞，受精卵。胚胎的发育始于卵子开始分裂产生许多细胞。不同的细胞在胚胎发育过程中被指定-它们基本上是通过在早期胚胎中起作用的分子信号来告诉它们做什么和变成什么。这些信号通常会导致特定的基因被“打开”或“关闭”。如果一个基因是“开”的，它就被表达，这意味着它是从细胞核中的DNA活跃地转录的。在转录过程中，DNA被复制成RNA。这些RNA转录物通常编码蛋白质，并且RNA通过复杂的细胞机制翻译成蛋白质。蛋白质是细胞中的“推动者和震动者”，它们定义了一个细胞，它们有特定的工作要做。例如，骨骼肌的收缩是由快速和缓慢收缩纤维（由蛋白质组成）介导的。肌肉是一种可塑性很强的组织，根据你是训练成为100米短跑运动员还是马拉松运动员，不同类型的肌肉蛋白质将被表达。肌肉也有自我修复（再生）的能力，例如在肌肉丢失后，但当肌肉再次使用时，它会很快恢复。我们对控制胚胎中肌肉发育的分子感兴趣，已知其中一些（包括我们以前发现的一些，称为“Wnt”）也在肌肉再生过程中使用。我们特别研究了一类RNA分子，它们不被翻译成蛋白质。RNA分子本身具有重要的功能。这些非编码RNA是最近发现的，因为它们非常小，所以被称为microRNA（miRs）。它们在植物和动物中被发现，这意味着它们是生命最基本的机器的一部分，在所有细胞中都有非常重要和基本的工作。事实证明是这样的，事实上microRNA控制着其他编码RNA是否被翻译成蛋白质。人们正在进行大量的研究，以帮助了解这是如何发生的，并揭示以这种方式控制的细胞过程的类型。我们的研究调查了细胞如何在发育中的脊椎动物胚胎中变得彼此不同。特别是，我们研究了控制细胞从多能前体分化为骨骼肌的决定的基因和分子，而不是例如骨骼。我们最近发现，这些新的microRNA中有两种（目前已知的microRNA有400多种）只存在于胚胎中的那些细胞中，这些细胞将继续制造骨骼肌，我们想了解这些microRNA的作用是什么。我们已经弄清楚了microRNA本身的产生是如何被“打开”或“关闭”的，我们已经确定了一些由microRNA控制的基因（“靶标”）。理想情况下，我们希望确定所有的靶基因，我们还需要了解它们如何反过来影响骨骼肌。总的来说，我们将了解胚胎如何使正常，健康，工作的肌肉，这将在长期受益的人谁患有各种肌肉退行性疾病或年龄相关的肌肉损失。

项目成果

Third Report on Chicken Genes and Chromosomes 2015.

• DOI: 10.1159/000430927
• 发表时间: 2015
• 期刊: Cytogenetic and genome research
• 影响因子: 1.7
• 作者: Schmid M;Smith J;Burt DW;Aken BL;Antin PB;Archibald AL;Ashwell C;Blackshear PJ;Boschiero C;Brown CT;Burgess SC;Cheng HH;Chow W;Coble DJ;Cooksey A;Crooijmans RP;Damas J;Davis RV;de Koning DJ;Delany ME;Derrien T;Desta TT;Dunn IC;Dunn M;Ellegren H;Eöry L;Erb I;Farré M;Fasold M;Fleming D;Flicek P;Fowler KE;Frésard L;Froman DP;Garceau V;Gardner PP;Gheyas AA;Griffin DK;Groenen MA;Haaf T;Hanotte O;Hart A;Häsler J;Hedges SB;Hertel J;Howe K;Hubbard A;Hume DA;Kaiser P;Kedra D;Kemp SJ;Klopp C;Kniel KE;Kuo R;Lagarrigue S;Lamont SJ;Larkin DM;Lawal RA;Markland SM;McCarthy F;McCormack HA;McPherson MC;Motegi A;Muljo SA;Münsterberg A;Nag R;Nanda I;Neuberger M;Nitsche A;Notredame C;Noyes H;O'Connor R;O'Hare EA;Oler AJ;Ommeh SC;Pais H;Persia M;Pitel F;Preeyanon L;Prieto Barja P;Pritchett EM;Rhoads DD;Robinson CM;Romanov MN;Rothschild M;Roux PF;Schmidt CJ;Schneider AS;Schwartz MG;Searle SM;Skinner MA;Smith CA;Stadler PF;Steeves TE;Steinlein C;Sun L;Takata M;Ulitsky I;Wang Q;Wang Y;Warren WC;Wood JM;Wragg D;Zhou H
• 通讯作者: Zhou H

myomiR-dependent switching of BAF60 variant incorporation into Brg1 chromatin remodeling complexes during embryo myogenesis.

在胚胎肌发生过程中，BAF60变体掺入BAF60变体重塑络合物中的肌瘤依赖性切换。

• DOI: 10.1242/dev.108787
• 发表时间: 2014-09
• 期刊: Development (Cambridge, England)
• 作者: Goljanek-Whysall K;Mok GF;Fahad Alrefaei A;Kennerley N;Wheeler GN;Münsterberg A
• 通讯作者: Münsterberg A

Reducing ligation bias of small RNAs in libraries for next generation sequencing.

• DOI: 10.1186/1758-907x-3-4
• 发表时间: 2012-05-30
• 期刊: Silence
• 作者: Sorefan K;Pais H;Hall AE;Kozomara A;Griffiths-Jones S;Moulton V;Dalmay T
• 通讯作者: Dalmay T

Detailed expression profile of all six Glypicans and their modifying enzyme Notum during chick embryogenesis and their role in dorsal-ventral patterning of the neural tube.

鸡胚胎发生过程中所有六种磷脂酰肌醇蛋白聚糖及其修饰酶 Notum 的详细表达谱及其在神经管背腹模式中的作用。

• DOI: 10.1016/j.gene.2017.01.032
• 发表时间: 2017
• 期刊: Gene
• 影响因子: 3.5
• 作者: Saad K