G-quadruplex structures mark human regulatory chromatin
G-quadruplex structures mark human regulatory chromatin
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DOI：
10.1038/ng.3662
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发表时间：
2016-10-01
期刊：
影响因子：
30.8
通讯作者：
Balasubramanian, Shankar
中科院分区：
文献类型：
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作者：
Hansel-Hertsch, Robert;Beraldi, Dario;Balasubramanian, Shankar
G-四链体 (G4) 结构基序与转录 (1,2)、复制 (3) 和基因组不稳定性 (4,5) 相关，并且与癌症和其他疾病 (6-8) 有关。然而，在内源染色质环境中证明 G4 结构的真实形成至关重要(9,10)。在此，我们通过开发 G4 ChIP-seq 来解决这个问题，G4 ChIP-seq 是一种基于抗体的 G4 染色质免疫沉淀和高通量测序方法。我们在人类染色质中发现了类似于 10,000 个 G4 结构，主要位于核小体耗尽的调节区域。 G4 结构在高度转录基因的启动子和 5' UTR 中富集，特别是在与癌症相关的基因和体细胞拷贝数扩增（例如 MYC）中。引人注目的是，从头开始和增强的 G4 形成与转录活性增加有关，如 HDAC 抑制剂诱导的染色质松弛所示，以及与正常细胞状态相比在永生化细胞中观察到的情况。我们的研究结果表明，调节性、核小体耗尽的染色质和升高的转录塑造了内源性人类 G4 DNA 景观。
G-quadruplex (G4) structural motifs have been linked to transcription(1,2), replication(3) and genome instability(4,5) and are implicated in cancer and other diseases(6-8). However, it is crucial to demonstrate the bona fide formation of G4 structures within an endogenous chromatin context(9,10). Herein we address this through the development of G4 ChIP-seq, an antibody-based G4 chromatin immunoprecipitation and high-throughput sequencing approach. We find similar to 10,000 G4 structures in human chromatin, predominantly in regulatory, nucleosome-depleted regions. G4 structures are enriched in the promoters and 5' UTRs of highly transcribed genes, particularly in genes related to cancer and in somatic copy number amplifications, such as MYC. Strikingly, de novo and enhanced G4 formation are associated with increased transcriptional activity, as shown by HDAC inhibitor-induced chromatin relaxation and observed in immortalized as compared to normal cellular states. Our findings show that regulatory, nucleosome-depleted chromatin and elevated transcription shape the endogenous human G4 DNA landscape.