Ligand-induced native G-quadruplex stabilization impairs transcription initiation.
Ligand-induced native G-quadruplex stabilization impairs transcription initiation.
复制标题
DOI：
10.1101/gr.275431.121
复制
发表时间：
2021-09
期刊：
影响因子：
7
通讯作者：
Liang K
中科院分区：
文献类型：
--
作者：
Li C;Wang H;Yin Z;Fang P;Xiao R;Xiang Y;Wang W;Li Q;Huang B;Huang J;Liang K
g -四plex （G4s）是通过鸟嘌呤自结合形成的非规范DNA二级结构，在基因组中广泛分布。G4参与包括基因转录在内的多种生物学过程，G4靶向配体是dna靶向治疗的潜在治疗剂。然而，G4s在转录调控中的确切作用的全基因组研究仍然缺乏。在此，我们建立了一种敏感的G4-CUT&Tag方法，用于高分辨率和特异性的天然G4s全基因组分析。我们发现原生G4信号具有细胞类型特异性，并与携带活性表观遗传修饰的转录调控元件相关。药物诱导的启动子-近端RNA聚合酶II暂停促进附近G4的形成。相比之下，G4靶向配体的G4稳定性全局降低了基因启动子处RNA聚合酶II的占用以及新生RNA合成。此外，配体诱导的G4稳定调节染色质状态，并通过抑制一般转录因子加载启动子来阻碍转录起始。总之，我们的研究揭示了原生G4动力学和基因转录之间的相互全基因组调控，这将加深我们对G4生物学的理解，以治疗人类疾病中的G4。
G-quadruplexes (G4s) are noncanonical DNA secondary structures formed through the self-association of guanines, and G4s are distributed widely across the genome. G4 participates in multiple biological processes including gene transcription, and G4-targeted ligands serve as potential therapeutic agents for DNA-targeted therapies. However, genome-wide studies of the exact roles of G4s in transcriptional regulation are still lacking. Here, we establish a sensitive G4-CUT&Tag method for genome-wide profiling of native G4s with high resolution and specificity. We find that native G4 signals are cell type–specific and are associated with transcriptional regulatory elements carrying active epigenetic modifications. Drug-induced promoter-proximal RNA polymerase II pausing promotes nearby G4 formation. In contrast, G4 stabilization by G4-targeted ligands globally reduces RNA polymerase II occupancy at gene promoters as well as nascent RNA synthesis. Moreover, ligand-induced G4 stabilization modulates chromatin states and impedes transcription initiation via inhibition of general transcription factors loading to promoters. Together, our study reveals a reciprocal genome-wide regulation between native G4 dynamics and gene transcription, which will deepen our understanding of G4 biology toward therapeutically targeting G4s in human diseases.
登录
查看更多内容
DOI：
10.1038/nrg3296
发表时间：
2012-11
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.5
作者：
Liang K;Smith ER;Aoi Y;Stoltz KL;Katagi H;Woodfin AR;Rendleman EJ;Marshall SA;Murray DC;Wang L;Ozark PA;Mishra RK;Hashizume R;Schiltz GE;Shilatifard A
通讯作者：
Shilatifard A
DOI：
10.1074/mcp.m114.041012
发表时间：
2015-01
期刊：
Molecular & cellular proteomics : MCP
影响因子：
--
作者：
Keilhauer EC;Hein MY;Mann M
通讯作者：
Mann M
影响因子：
64.8
作者：
Chen MC;Tippana R;Demeshkina NA;Murat P;Balasubramanian S;Myong S;Ferré-D'Amaré AR
通讯作者：
Ferré-D'Amaré AR
影响因子：
2.9
作者：
Anantha, NV;Azam, M;Sheardy, RD
通讯作者：
Sheardy, RD