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

点击翻译按钮获取中文摘要

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.