Unravelling the microRNA-chromatin remodelling circuitry that drives myogenesis

解开驱动肌生成的 microRNA-染色质重塑电路

• 批准号: BB/N007034/1
• 负责人: Andrea Munsterberg
• 金额: $ 66.37万
• 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: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FN007034%2F1
• 关键词: Unravelling; microRNA; chromatin; remodelling; circuitry

THE 'BIG' PICTURE: 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. The cells are initially multi-potent, but they gradually become specialized and restricted to perform specific tasks. This cell-lineage restriction is regulated by factors that influence the activity of genes and regulate the accessibility of the genome in the nucleus of the cell. Some genes are 'off' and DNA is packaged tightly, other regions are more loosely packaged and therefore 'open' and accessible to factors that can switch a gene 'on'. If a gene is 'on', it means the gene will be expressed and actively transcribed. The regulation of gene activity is crucial for cells to become specialised in their functions.THE QUESTION: We are interested in the molecules that control the development of muscle in an embryo. Why do progenitor cells develop into muscle rather than other related cell types, such as fat, cartilage, bone or connective tissue? Our studies focus on a class of RNA molecules, which we found regulate the factors that control the accessibility of the genome. These non-coding RNAs were discovered recently and because they are very small, they were called 'microRNAs' (miRs), they control the translation of genes into protein - a fundamental job required in all cells. WHY IS THIS IMPORTANT? Regulating the accessibility of the genome is very important during cellular differentiation in embryo development. Understanding this genetic programme is also important for muscle regeneration and repair after injury or long-term bed rest. The process of cell lineage determination is also crucial for the differentiation of stem cells, or for the reprogramming of already specialized cells towards a different fate. We know many of the components involved, but we still do not understand in detail how they function, or how they are put together. We recently discovered that microRNAs influence the composition of these 'reprogramming' complexes and we have a well-defined system in which to study this more systematically. This offers the unique opportunity to identify all of the important players and will provide a deeper mechanistic insight at the molecular level. This is needed, not only to fully understand how specialized cells form in developing embryos, but also to be able to use stem cells in regenerative medicine and tissue engineering, emerging fields of increasing importance and with significant future potential for medicine and health. We will learn how an embryo makes normal, healthy, working muscle and this will in the long-term benefit people who suffer from various conditions that affect muscle health or help to alleviate age related muscle-loss.EXPERIMENTAL MODEL SYSTEM: We use very early chick embryos, which are very similar in morphology to early human embryos, to investigate the roles of important microRNAs present in muscle. We will use protocols to identify how they affect the the factors that control the accessibility of the genome in naïve and differentiating muscle cells. We have experience with these state-of-the-art molecular methods in the chick embryo, an accessible experimental system and we have assembled a highly skilled team of researchers to execute this programme of research.

“大”图：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。这些细胞最初是多能的，但它们逐渐变得特化，并被限制执行特定的任务。这种细胞谱系限制受到影响基因活性和调节细胞核中基因组可及性的因素的调节。一些基因是“关闭”的，DNA是紧密包装的，其他区域包装得更松散，因此是“开放”的，可以接触到可以打开基因的因子。如果一个基因是“开”，这意味着该基因将被表达和积极转录。基因活性的调节对于细胞功能的专门化至关重要。问题：我们对控制胚胎肌肉发育的分子感兴趣。为什么祖细胞发育成肌肉而不是其他相关的细胞类型，如脂肪，软骨，骨或结缔组织？我们的研究集中在一类RNA分子上，我们发现它们调节着控制基因组可及性的因素。这些非编码RNA是最近发现的，由于它们非常小，因此被称为“微小RNA”（miRs），它们控制基因翻译成蛋白质--这是所有细胞都需要的基本工作。为什么这很重要？调控基因组的可及性在胚胎发育的细胞分化过程中非常重要。了解这种遗传程序对于受伤或长期卧床休息后的肌肉再生和修复也很重要。细胞谱系确定的过程对于干细胞的分化或对于已经特化的细胞朝向不同命运的重编程也是至关重要的。我们知道许多相关的组成部分，但我们仍然不了解它们如何运作，或者它们是如何组合在一起的。我们最近发现microRNA影响这些“重编程”复合物的组成，我们有一个明确的系统来更系统地研究这一点。这为识别所有重要参与者提供了独特的机会，并将在分子水平上提供更深入的机制见解。这是必要的，不仅要充分了解专门的细胞如何在胚胎发育中形成，而且要能够在再生医学和组织工程中使用干细胞，这些新兴领域越来越重要，未来在医学和健康方面具有巨大的潜力。我们将了解胚胎如何使正常的，健康的，工作的肌肉，这将在长期受益的人谁遭受的各种条件，影响肌肉健康或有助于减轻年龄相关的肌肉损失。实验模型系统：我们使用非常早期的鸡胚胎，这是非常相似的形态早期人类胚胎，调查肌肉中存在的重要microRNA的作用。我们将使用协议来确定它们如何影响控制幼稚和分化肌细胞中基因组可及性的因素。我们在鸡胚中拥有这些最先进的分子方法的经验，这是一个可访问的实验系统，我们已经组建了一支高技能的研究人员团队来执行这项研究计划。

项目成果

The Pax6 master control gene initiates spontaneous retinal development via a self-organising Turing network

Pax6主控基因通过自组织图灵网络启动自发视网膜发育

• DOI: 10.1101/583807
• 发表时间: 2019
• 作者: Grocott T

Characterising open chromatin in chick embryos identifies cis-regulatory elements important for paraxial mesoderm formation and axis extension.

• DOI: 10.1038/s41467-021-21426-7
• 发表时间: 2021-02-19
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Mok GF;Folkes L;Weldon SA;Maniou E;Martinez-Heredia V;Godden AM;Williams RM;Sauka-Spengler T;Wheeler GN;Moxon S;Münsterberg AE
• 通讯作者: Münsterberg AE

The Pax6 master control gene initiates spontaneous retinal development via a self-organising Turing network.

• DOI: 10.1242/dev.185827
• 发表时间: 2020-12-23
• 期刊: Development (Cambridge, England)
• 作者: Grocott T;Lozano-Velasco E;Mok GF;Münsterberg AE
• 通讯作者: Münsterberg AE

4D imaging reveals stage dependent random and directed cell motion during somite morphogenesis

4D 成像揭示体节形态发生过程中阶段依赖性随机和定向细胞运动

• DOI: 10.1101/280883
• 发表时间: 2018
• 作者: McColl J

4D imaging reveals stage dependent random and directed cell motion during somite morphogenesis.

• DOI: 10.1038/s41598-018-31014-3
• 发表时间: 2018-08-23
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: McColl J;Mok GF;Lippert AH;Ponjavic A;Muresan L;Münsterberg A
• 通讯作者: Münsterberg A