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

• Published in: Nature communications 2021-09, Vol.12 (1), p.5548-5548, Article 5548
• Main Authors: Jiang, Yuhan, Li, Yixiao, Liu, Cheng, Zhang, Lei, Lv, Danyu, Weng, Yejing, Cheng, Zhongyi, Chen, Xiangmei, Zhan, Jun, Zhang, Hongquan
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/1; 13/109; 13/89; 14/19; 140/58; 38/47; 631/80/458; 631/92/458; 64/60; 82/51; 82/80; 82/81; Acylation; AKT protein; Biological effects; Biosynthesis; Chromatin; CREB-binding protein; Cyclic AMP response element-binding protein; Gene expression; Health risks; Hepatocytes; Histone deacetylase; Histones; Humanities and Social Sciences; Isoniazid; Liver; Liver cancer; Lysine; Mass spectrometry; Mass spectroscopy; Metabolites; multidisciplinary; Post-translation; Science; Science (multidisciplinary); Side effects; Signal transduction; TOR protein; Transcription; Tuberculosis
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-25867-y

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 (K inic ), 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 K inic sites in histones in HepG2 cells. Acetyltransferases CREB-binding protein (CBP) and P300 catalyse histone K inic , while histone deacetylase HDAC3 functions as a deisonicotinylase. Notably, MNase sensitivity assay and RNA-seq analysis show that histone K inic relaxes chromatin structure and promotes gene transcription. INH-mediated histone K inic 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 K inic 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. Isoniazid (INH) is an anti-tuberculosis drug; however the underlying cause of its various side effects are not understood. Here the authors identified lysine isonicotinylation as a histone modification on chromatin that is metabolically regulated by INH and its metabolites.