Wilson Stephen, Filipp Fabian Volker
Systems Biology and Cancer Metabolism, Program for Quantitative Systems Biology, University of California Merced, 2500 North Lake Road, Merced, CA 95343 USA.
NPJ Syst Biol Appl. 2018 Jul 1;4:24. doi: 10.1038/s41540-018-0061-4. eCollection 2018.
Coordinated experiments focused on transcriptional responses and chromatin states are well-equipped to capture different epigenomic and transcriptomic levels governing the circuitry of a regulatory network. We propose a workflow for the genome-wide identification of epigenomic and transcriptional cooperation to elucidate transcriptional networks in cancer. Gene promoter annotation in combination with network analysis and sequence-resolution of enriched transcriptional motifs in epigenomic data reveals transcription factor families that act synergistically with epigenomic master regulators. By investigating complementary omics levels, a close teamwork of the transcriptional and epigenomic machinery was discovered. The discovered network is tightly connected and surrounds the histone lysine demethylase KDM3A, basic helix-loop-helix factors MYC, HIF1A, and SREBF1, as well as differentiation factors AP1, MYOD1, SP1, MEIS1, ZEB1, and ELK1. In such a cooperative network, one component opens the chromatin, another one recognizes gene-specific DNA motifs, others scaffold between histones, cofactors, and the transcriptional complex. In cancer, due to the ability to team up with transcription factors, epigenetic factors concert mitogenic and metabolic gene networks, claiming the role of a cancer master regulators or epioncogenes. Significantly, specific histone modification patterns are commonly associated with open or closed chromatin states, and are linked to distinct biological outcomes by transcriptional activation or repression. Disruption of patterns of histone modifications is associated with the loss of proliferative control and cancer. There is tremendous therapeutic potential in understanding and targeting histone modification pathways. Thus, investigating cooperation of chromatin remodelers and the transcriptional machinery is not only important for elucidating fundamental mechanisms of chromatin regulation, but also necessary for the design of targeted therapeutics.
专注于转录反应和染色质状态的协同实验，能够很好地捕捉调控网络回路的不同表观基因组和转录组水平。我们提出了一种全基因组范围内识别表观基因组和转录协同作用的工作流程，以阐明癌症中的转录网络。基因启动子注释与网络分析以及表观基因组数据中富集转录基序的序列解析相结合，揭示了与表观基因组主调控因子协同作用的转录因子家族。通过研究互补的组学水平，发现了转录和表观基因组机制之间紧密的协同合作关系。所发现的网络紧密相连，围绕着组蛋白赖氨酸去甲基化酶KDM3A、碱性螺旋-环-螺旋因子MYC、HIF1A和SREBF1，以及分化因子AP1、MYOD1、SP1、MEIS1、ZEB1和ELK1。在这样一个协同网络中，一个组分打开染色质，另一个组分识别基因特异性DNA基序，其他组分则在组蛋白、辅因子和转录复合物之间起支架作用。在癌症中，由于能够与转录因子协同作用，表观遗传因子协调有丝分裂和代谢基因网络，从而发挥癌症主调控因子或表观癌基因的作用。值得注意的是，特定的组蛋白修饰模式通常与开放或封闭的染色质状态相关，并通过转录激活或抑制与不同的生物学结果相联系。组蛋白修饰模式的破坏与增殖控制的丧失和癌症相关。理解和靶向组蛋白修饰途径具有巨大的治疗潜力。因此，研究染色质重塑因子与转录机制的协同作用不仅对于阐明染色质调控的基本机制很重要，而且对于靶向治疗的设计也是必要的。
