G-quadruplexes sense natural porphyrin metabolites for regulation of gene transcription and chromatin landscapes.
G-quadruplexes sense natural porphyrin metabolites for regulation of gene transcription and chromatin landscapes.
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DOI：
10.1186/s13059-022-02830-8
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发表时间：
2022-12-15
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影响因子：
12.3
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中科院分区：
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--
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G-四链体（G4 s）是一种独特的非经典核酸二级结构，与转录因子和染色质重塑因子相互作用，调控细胞类型特异性转录组和染色质景观。基于G4与天然卟啉之间的直接相互作用，我们建立了全基因组的方法来分析铁配体卟啉氯化血红素在染色质中的结合位置。氯化血红素促进全基因组G4形成，损害转录起始，并改变染色质景观，包括减少H3 K27 ac和H3 K4 me 3在启动子处的修饰。有趣的是，G4状态不参与经典的氯化血红素-BACH 1-NRF 2介导的增强子激活过程，突出了前所未有的G4依赖性转录代谢调控机制。此外，氯化血红素治疗诱导肝细胞中的特定基因表达谱，强调卟啉代谢控制基因转录的体内潜力。这些研究表明，G4作为细胞中天然卟啉代谢物的传感器，揭示了G4依赖的基因转录和染色质景观的代谢调控机制，这将加深我们对G4生物学和细胞代谢物对基因调控的贡献的认识。在线版本包含补充材料，可通过10.1186/s13059-022-02830-8获得。
G-quadruplexes (G4s) are unique noncanonical nucleic acid secondary structures, which have been proposed to physically interact with transcription factors and chromatin remodelers to regulate cell type-specific transcriptome and shape chromatin landscapes. Based on the direct interaction between G4 and natural porphyrins, we establish genome-wide approaches to profile where the iron-liganded porphyrin hemin can bind in the chromatin. Hemin promotes genome-wide G4 formation, impairs transcription initiation, and alters chromatin landscapes, including decreased H3K27ac and H3K4me3 modifications at promoters. Interestingly, G4 status is not involved in the canonical hemin-BACH1-NRF2-mediated enhancer activation process, highlighting an unprecedented G4-dependent mechanism for metabolic regulation of transcription. Furthermore, hemin treatment induces specific gene expression profiles in hepatocytes, underscoring the in vivo potential for metabolic control of gene transcription by porphyrins. These studies demonstrate that G4 functions as a sensor for natural porphyrin metabolites in cells, revealing a G4-dependent mechanism for metabolic regulation of gene transcription and chromatin landscapes, which will deepen our knowledge of G4 biology and the contribution of cellular metabolites to gene regulation. The online version contains supplementary material available at 10.1186/s13059-022-02830-8.
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