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

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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.
Funding Information
  • National Natural Science Foundation of China (81730071, 81972616, 81972609, 81773199)
  • Chinese Ministry of Science and Technology | Department of S and T for Social Development (2016YFC1302103, 2015CB553906)
  • Chinese Ministry of Science and Technology | Department of S and T for Social Development
  • Natural Science Foundation of Beijing Municipality (7171005)
  • Peking University (BMU2018JC004, BMU20120314, PKU2021LCXQ023)

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