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Epigenetic regulation of cell fate determination and functional specification during lung development

肺发育过程中细胞命运决定和功能规范的表观遗传调控

基本信息

批准号：
164686135
负责人：
Professor Dr. Guillermo Barreto, Ph.D.
金额：
--
依托单位：
IMoPA Ingénierie Moléculaire et Physiopathologie Articulaire
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2010
资助国家：
德国
起止时间：
2009-12-31 至 2016-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/164686135?language=en
关键词：
Epigenetic regulation cell fate determination

项目摘要

Chromatin constitutes the physiological template for all kinds of DNA-dependent processes including replication, recombination, repair and transcription. However, chromatin represents a strong barrier to sequence specific recognition sites on the DNA thereby increasing the complexity of regulation of DNA-dependent processes. To overcome this barrier, it is a prerequisite to open the higher order chromatin structure so that regulators of the above mentioned processes can access their recognition sites on the DNA and execute their function. It is well known that chromatin mediated transcription regulation involves histone modifications, chromatin remodeling and DNA methylation. However, the precise biological function of non-histone chromatin-associated proteins is not clear. The high mobility group (HMG) proteins are the most abundant non-histone chromatin-associated proteins. With the research program proposed here we will decipher the mechanism of transcriptional regulation mediated by the high mobility group AT-hook protein 2 (HMGA2). Our preliminary work highlights a mechanism in which histone phosphorylation, mediated by the kinase ataxia telangiectasia mutated (ATM), anticipates transcriptional initiation. Moreover, our results link phosphorylation of the core histone variant H2AX at serine 139, a histone modification that is commonly associated with DNA double strand breaks, to transcriptional activation. This is an entirely new function for this histone modification. The functional connection between HMGA2, ATM and H2AX is novel and with the research program proposed here we will demonstrate that this is a general mechanism of transcription initiation.The biological relevance of the mechanism of transcriptional regulation that we propose is supported by recent publications in high profile journals in which it has been shown that HMG proteins are required for canonical WNT signaling during lung development (Singh et al., 2014 BMC Biol), regulate myoblast proliferation and myogenesis (Li et al., 2012 Dev Cell), promote endothelial progenitor cell-mediated neurovascular remodeling during stroke recovery (Hayakawa et al., 2012 PNAS), are important for transcription initiation (Xu et al., 2011 Genes Dev), play a role in nucleic-acid-mediated innate immune responses (Yanai et al., 2009 Nature) and inflammation (Lu et al., 2012 Nature). Moreover, Hmga2 is a potential oncogene in lung cancer (Winslow et al., 2011 Nature and Kumar et al., 2013 Nature). Thus, our work will be of great interest for a large audience including researchers in other related disciplines such as cancer and, in general, medicine.

染色质构成了各种DNA依赖性过程的生理模板，包括复制、重组、修复和转录。然而，染色质代表了对DNA上序列特异性识别位点的强屏障，从而增加了DNA依赖性过程的调节的复杂性。为了克服这一障碍，打开更高级的染色质结构是一个先决条件，以便上述过程的调节剂可以进入DNA上的识别位点并执行其功能。众所周知，染色质介导的转录调控涉及组蛋白修饰、染色质重塑和DNA甲基化。然而，非组蛋白染色质相关蛋白的确切生物学功能尚不清楚。高迁移率族蛋白（HMG）是最丰富的非组蛋白染色质相关蛋白。通过本研究计划，我们将对高迁移率族AT-钩蛋白2（HMGA 2）介导的转录调控机制进行初步的研究。我们的初步工作突出了一个机制，其中组蛋白磷酸化，介导的激酶共济失调毛细血管扩张突变（ATM），预期转录启动。此外，我们的研究结果将核心组蛋白变体H2AX在丝氨酸139处的磷酸化（一种通常与DNA双链断裂相关的组蛋白修饰）与转录激活联系起来。这是这种组蛋白修饰的全新功能。HMGA 2、ATM和H2AX是新的，并与这里提出的研究计划，我们将证明这是一个一般的转录起始机制，我们提出的转录调控机制的生物相关性是由最近的出版物在高知名度的期刊，其中已经表明，HMG蛋白是所需的典型WNT信号在肺发育（Singh等人，2014 BMC Biol），调节成肌细胞增殖和肌生成（Li等人，2012 Dev Cell），在中风恢复期间促进内皮祖细胞介导的神经血管重塑（Hayakawa等人，2012 PNAS），对于转录起始是重要的（Xu et al.，2011 Genes Dev），在核酸介导的先天免疫应答中起作用（柳井等人，2009 Nature）和炎症（Lu等人，2012 Nature）。此外，Hmga 2是肺癌中的潜在致癌基因（温斯洛等人，2011 Nature和Kumar等人，2013 Nature）。因此，我们的工作将引起广大观众的极大兴趣，包括其他相关学科的研究人员，如癌症和一般医学。