Isonicotinylation is a histone mark induced by the anti-tuberculosis first-line drug isoniazid

Yuhan Jiang, Yixiao Li, Cheng Liu, Lei Zhang, Danyu Lv, Yejing Weng, Zhongyi Cheng, Xiangmei Chen, Jun Zhan and Hongquan Zhang ()
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Yuhan Jiang: Peking University Health Science Center
Yixiao Li: Peking University Health Science Center
Cheng Liu: Peking University Health Science Center
Lei Zhang: Peking University Health Science Center
Danyu Lv: Peking University Health Science Center
Yejing Weng: Jingjie PTM BioLab Co. Ltd., Hangzhou Economic and Technological Development Area
Zhongyi Cheng: Jingjie PTM BioLab Co. Ltd., Hangzhou Economic and Technological Development Area
Xiangmei Chen: Peking University Health Science Center
Jun Zhan: Peking University Health Science Center
Hongquan Zhang: Peking University Health Science Center

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract Isoniazid (INH) is a first-line anti-tuberculosis drug used for nearly 70 years. However, the mechanism underlying the side effects of INH has remained elusive. Here, we report that INH and its metabolites induce a post-translational modification (PTM) of histones, lysine isonicotinylation (Kinic), also called 4-picolinylation, in cells and mice. INH promotes the biosynthesis of isonicotinyl-CoA (Inic-CoA), a co-factor of intracellular isonicotinylation. Mass spectrometry reveals 26 Kinic sites in histones in HepG2 cells. Acetyltransferases CREB-binding protein (CBP) and P300 catalyse histone Kinic, while histone deacetylase HDAC3 functions as a deisonicotinylase. Notably, MNase sensitivity assay and RNA-seq analysis show that histone Kinic relaxes chromatin structure and promotes gene transcription. INH-mediated histone Kinic upregulates PIK3R1 gene expression and activates the PI3K/Akt/mTOR signalling pathway in liver cancer cells, linking INH to tumourigenicity in the liver. We demonstrate that Kinic is a histone acylation mark with a pyridine ring, which may have broad biological effects. Therefore, INH-induced isonicotinylation potentially accounts for the side effects in patients taking INH long-term for anti-tuberculosis therapy, and this modification may increase the risk of cancer in humans.

Date: 2021
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DOI: 10.1038/s41467-021-25867-y

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