Gene activation guided by nascent RNA-bound transcription factors

Ying Liang, Haiyue Xu, Tao Cheng, Yujuan Fu, Hanwei Huang, Wenchang Qian, Junyan Wang, Yuenan Zhou, Pengxu Qian, Yafei Yin, Pengfei Xu, Wei Zou () and Baohui Chen ()
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Ying Liang: Zhejiang University School of Medicine
Haiyue Xu: Zhejiang University School of Medicine
Tao Cheng: Zhejiang University School of Medicine
Yujuan Fu: Zhejiang University School of Medicine
Hanwei Huang: Zhejiang University School of Medicine
Wenchang Qian: Zhejiang University School of Medicine
Junyan Wang: Zhejiang University School of Medicine
Yuenan Zhou: Zhejiang University School of Medicine
Pengxu Qian: Zhejiang University School of Medicine
Yafei Yin: Zhejiang University School of Medicine
Pengfei Xu: Zhejiang University School of Medicine
Wei Zou: Zhejiang University School of Medicine
Baohui Chen: Zhejiang University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Technologies for gene activation are valuable tools for the study of gene functions and have a wide range of potential applications in bioengineering and medicine. In contrast to existing methods based on recruiting transcriptional modulators via DNA-binding proteins, we developed a strategy termed Narta (nascent RNA-guided transcriptional activation) to achieve gene activation by recruiting artificial transcription factors (aTFs) to transcription sites through nascent RNAs of the target gene. Using Narta, we demonstrate robust activation of a broad range of exogenous and endogenous genes in various cell types, including zebrafish embryos, mouse and human cells. Importantly, the activation is reversible, tunable and specific. Moreover, Narta provides better activation potency of some expressed genes than CRISPRa and, when used in combination with CRISPRa, has an enhancing effect on gene activation. Quantitative imaging illustrated that nascent RNA-directed aTFs could induce the high-density assembly of coactivators at transcription sites, which may explain the larger transcriptional burst size induced by Narta. Overall, our work expands the gene activation toolbox for biomedical research.

Date: 2022
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DOI: 10.1038/s41467-022-35041-7

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