HBO1 catalyzes lysine lactylation and mediates histone H3K9la to regulate gene transcription

Ziping Niu, Chen Chen (), Siyu Wang, Congcong Lu, Zhiyue Wu, Aiyuan Wang, Jing Mo, Jianji Zhang, Yanpu Han, Ye Yuan, Yingao Zhang, Yong Zang, Chaoran He, Xue Bai, Shanshan Tian, Guijin Zhai, Xudong Wu and Kai Zhang ()
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Ziping Niu: School of Basic Medical Sciences, Tianjin Medical University
Chen Chen: School of Basic Medical Sciences, Tianjin Medical University
Siyu Wang: School of Basic Medical Sciences, Tianjin Medical University
Congcong Lu: College of Life Sciences, Nankai University
Zhiyue Wu: School of Basic Medical Sciences, Tianjin Medical University
Aiyuan Wang: School of Basic Medical Sciences, Tianjin Medical University
Jing Mo: Tianjin Medical University
Jianji Zhang: School of Basic Medical Sciences, Tianjin Medical University
Yanpu Han: School of Basic Medical Sciences, Tianjin Medical University
Ye Yuan: School of Basic Medical Sciences, Tianjin Medical University
Yingao Zhang: School of Basic Medical Sciences, Tianjin Medical University
Yong Zang: School of Basic Medical Sciences, Tianjin Medical University
Chaoran He: School of Basic Medical Sciences, Tianjin Medical University
Xue Bai: School of Basic Medical Sciences, Tianjin Medical University
Shanshan Tian: School of Basic Medical Sciences, Tianjin Medical University
Guijin Zhai: School of Basic Medical Sciences, Tianjin Medical University
Xudong Wu: School of Basic Medical Sciences, Tianjin Medical University
Kai Zhang: School of Basic Medical Sciences, Tianjin Medical University

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Lysine lactylation (Kla) links metabolism and gene regulation and plays a key role in multiple biological processes. However, the regulatory mechanism and functional consequence of Kla remain to be explored. Here, we report that HBO1 functions as a lysine lactyltransferase to regulate transcription. We show that HBO1 catalyzes the addition of Kla in vitro and intracellularly, and E508 is a key site for the lactyltransferase activity of HBO1. Quantitative proteomic analysis further reveals 95 endogenous Kla sites targeted by HBO1, with the majority located on histones. Using site-specific antibodies, we find that HBO1 may preferentially catalyze histone H3K9la and scaffold proteins including JADE1 and BRPF2 can promote the enzymatic activity for histone Kla. Notably, CUT&Tag assays demonstrate that HBO1 is required for histone H3K9la on transcription start sites (TSSs). Besides, the regulated Kla can promote key signaling pathways and tumorigenesis, which is further supported by evaluating the malignant behaviors of HBO1- knockout (KO) tumor cells, as well as the level of histone H3K9la in clinical tissues. Our study reveals HBO1 serves as a lactyltransferase to mediate a histone Kla-dependent gene transcription.

Date: 2024
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DOI: 10.1038/s41467-024-47900-6

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