Elucidating the molecular basis of gene silencing by an ORC-HP1 interaction and their contribution to human health disorders

阐明 ORC-HP1 相互作用导致基因沉默的分子基础及其对人类健康疾病的影响

• 批准号: BB/M003760/1
• 负责人: Christian Speck
• 金额: $ 50.24万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FM003760%2F1
• 关键词: Elucidating; molecular; basis; gene; silencing

Some parts of our genome contain important information that represent a molecular building plan of the human body, while other regions contain little information or repetitive DNA sequences that do not appear to have any information associated with themselves. These less-informative regions of our genome are packed away and exist as highly compacted 'heterochromatin' in the nucleus of the cell. These 'heterochromatic' regions are covered by a protein called HP1, which helps the compaction process. HP1 is known to form oligomers, which act as a molecular glue, and therefore restrict access of other proteins to the compacted parts of the genome. Moreover, work over the last few years has shown that HP1 is not only found in condensed regions of the genome, but that HP1 can also compact smaller patches in accessible regions of the genome with important functions for gene regulation and genome stability. Thus HP1 acts as a global factor controlling access of other regulatory factors to the DNA. This way HP1 can affect many important processes in the cell - in the absence of HP1 the organism cannot survive. Misregulation of 'heterochromatin' and HP1 is involved in several diseases, including epigenetic diseases such as Friedreich's Ataxia or Facioscapulohumeral muscular dystrophy. Furthermore, HP1 has also been linked to aging, e.g. cells from older people or patients with an accelerated aging disease (Hutchinson-Gilford Progeria Syndrome) are characterized by a loss of key chromatin proteins, like HP1. In cancer, HP1 is frequently down regulated, which promotes tumorigenesis. It is not fully understood how HP1 is recruited to DNA, but this question is central for the normal function of HP1 and its role in disease. Recently it was shown that the origin-recognition complex (ORC), which is involved in DNA replication, is very important for HP1 recruitment to the genome. We want to explore the molecular mechanism that ORC employs to promote HP1 recruitment to chromatin. We will analyse the effect of ORC-HP1 interactions for its normal role in cells and in the context of the epigenetic disease, Friedreich's Ataxia, to understand the functional relevance of the complex. Finally, we will test if we can alter the activity of HP1 in cells with a peptide, which may spur the development of HP1 therapeutics. This project has not only the potential to identify a crucial mechanism of heterochromatin formation, the formation of the 'molecular glue', that regulates many processes in the cell, but also has additional implications for our understanding of cancer, epigenetic- and age related-diseases.

我们基因组的某些部分包含代表人体分子构建计划的重要信息，而其他区域包含很少的信息或重复的DNA序列，这些序列似乎没有任何与自身相关的信息。我们基因组中这些信息量较少的区域被打包起来，作为高度致密的“异染色质”存在于细胞核中。这些“异染色质”区域被称为HP 1的蛋白质覆盖，这有助于压缩过程。已知HP 1形成寡聚体，其充当分子胶，因此限制其他蛋白质进入基因组的紧密部分。此外，过去几年的研究表明，HP 1不仅存在于基因组的浓缩区域，而且HP 1还可以在基因组的可接近区域压缩较小的斑块，对基因调控和基因组稳定性具有重要功能。因此，HP 1作为一个全局因子控制其他调节因子进入DNA。这样，HP 1可以影响细胞中的许多重要过程-在没有HP 1的情况下，生物体无法生存。“异染色质”和HP 1的失调涉及几种疾病，包括表观遗传疾病，如弗里德赖希共济失调或面肩肱型肌营养不良症。此外，HP 1也与衰老有关，例如来自老年人或患有加速衰老疾病（Hutchinson-Gilford早衰综合征）的患者的细胞的特征在于关键染色质蛋白质的丢失，如HP 1。在癌症中，HP 1经常下调，这促进了肿瘤发生。目前尚不完全清楚HP 1是如何被招募到DNA中的，但这个问题对于HP 1的正常功能及其在疾病中的作用至关重要。最近的研究表明，参与DNA复制的起始识别复合物（origin-recognition complex，ORC）对于HP 1向基因组的募集非常重要。我们希望探索ORC促进HP 1向染色质募集的分子机制。我们将分析ORC-HP 1相互作用对其在细胞中的正常作用的影响，以及在表观遗传疾病Friedreich共济失调的背景下，以了解复合物的功能相关性。最后，我们将测试我们是否可以用肽改变细胞中HP 1的活性，这可能会刺激HP 1疗法的发展。该项目不仅有可能确定异染色质形成的关键机制，即调节细胞中许多过程的“分子胶”的形成，而且还对我们理解癌症，表观遗传和年龄相关疾病具有额外的意义。

项目成果

From structure to mechanism-understanding initiation of DNA replication.

• DOI: 10.1101/gad.298232.117
• 发表时间: 2017-06-01
• 期刊: Genes & development
• 影响因子: 10.5
• 作者: Riera A;Barbon M;Noguchi Y;Reuter LM;Schneider S;Speck C
• 通讯作者: Speck C

Transcriptional Activation of Pericentromeric Satellite Repeats and Disruption of Centromeric Clustering upon Proteasome Inhibition.

• DOI: 10.1371/journal.pone.0165873
• 发表时间: 2016
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Natisvili T;Yandim C;Silva R;Emanuelli G;Krueger F;Nageshwaran S;Festenstein R
• 通讯作者: Festenstein R

Targeting the Senescence-Overriding Cooperative Activity of Structurally Unrelated H3K9 Demethylases in Melanoma.

• DOI: 10.1016/j.ccell.2018.01.002
• 发表时间: 2018-02-12
• 期刊: Cancer cell
• 影响因子: 50.3
• 作者: Yu Y;Schleich K;Yue B;Ji S;Lohneis P;Kemper K;Silvis MR;Qutob N;van Rooijen E;Werner-Klein M;Li L;Dhawan D;Meierjohann S;Reimann M;Elkahloun A;Treitschke S;Dörken B;Speck C;Mallette FA;Zon LI;Holmen SL;Peeper DS;Samuels Y;Schmitt CA;Lee S
• 通讯作者: Lee S