Singh Indrabahadur, Ozturk Nihan, Cordero Julio, Mehta Aditi, Hasan Diya, Cosentino Claudia, Sebastian Carlos, Krüger Marcus, Looso Mario, Carraro Gianni, Bellusci Saverio, Seeger Werner, Braun Thomas, Mostoslavsky Raul, Barreto Guillermo
LOEWE Research Group Lung Cancer Epigenetic, Max-Planck-Institute for Heart and Lung Research, Parkstrasse 1, 61231 Bad Nauheim, Germany.
The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02118, USA.
Cell Res. 2015 Jul;25(7):837-50. doi: 10.1038/cr.2015.67. Epub 2015 Jun 5.
The eukaryotic genome is organized into chromatins, the physiological template for DNA-dependent processes including replication, recombination, repair, and transcription. Chromatin-mediated transcription regulation involves DNA methylation, chromatin remodeling, and histone modifications. However, chromatin also contains non-histone chromatin-associated proteins, of which the high-mobility group (HMG) proteins are the most abundant. Although it is known that HMG proteins induce structural changes of chromatin, the processes underlying transcription regulation by HMG proteins are poorly understood. Here we decipher the molecular mechanism of transcription regulation mediated by the HMG AT-hook 2 protein (HMGA2). We combined proteomic, ChIP-seq, and transcriptome data to show that HMGA2-induced transcription requires phosphorylation of the histone variant H2AX at S139 (H2AXS139ph; γ-H2AX) mediated by the protein kinase ataxia telangiectasia mutated (ATM). Furthermore, we demonstrate the biological relevance of this mechanism within the context of TGFβ1 signaling. The interplay between HMGA2, ATM, and H2AX is a novel mechanism of transcription initiation. Our results link H2AXS139ph to transcription, assigning a new function for this DNA damage marker. Controlled chromatin opening during transcription may involve intermediates with DNA breaks that may require mechanisms that ensure the integrity of the genome.
真核生物基因组被组织成染色质，它是包括复制、重组、修复和转录等依赖DNA的过程的生理模板。染色质介导的转录调控涉及DNA甲基化、染色质重塑和组蛋白修饰。然而，染色质中也含有非组蛋白染色质相关蛋白，其中高迁移率族（HMG）蛋白最为丰富。虽然已知HMG蛋白会诱导染色质的结构变化，但对HMG蛋白介导转录调控的潜在过程却了解甚少。在此，我们解析了由HMG AT-hook 2蛋白（HMGA2）介导的转录调控分子机制。我们整合了蛋白质组学、染色质免疫沉淀测序（ChIP-seq）和转录组数据，以表明HMGA2诱导的转录需要蛋白激酶共济失调毛细血管扩张突变蛋白（ATM）介导组蛋白变体H2AX在S139位点的磷酸化（H2AXS139ph；γ-H2AX）。此外，我们在转化生长因子β1（TGFβ1）信号传导背景下证明了这一机制的生物学相关性。HMGA2、ATM和H2AX之间的相互作用是一种新的转录起始机制。我们的结果将H2AXS139ph与转录联系起来，赋予了这个DNA损伤标记物一个新功能。转录过程中受控制的染色质开放可能涉及具有DNA断裂的中间体，这可能需要确保基因组完整性的机制。
