Isonicotinylation is a histone mark induced by the anti-tuberculosis first-line drug isoniazid.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 34545082.
- Also identified by DOI 10.1038/s41467-021-25867-y and PMC identifier 8452692.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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 (K<sub>inic</sub>), 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<sub>inic</sub> sites in histones in HepG2 cells. Acetyltransferases CREB-binding protein (CBP) and P300 catalyse histone K<sub>inic</sub>, while histone deacetylase HDAC3 functions as a deisonicotinylase. Notably, MNase sensitivity assay and RNA-seq analysis show that histone K<sub>inic</sub> relaxes chromatin structure and promotes gene transcription. INH-mediated histone K<sub>inic</sub> 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<sub>inic</sub> 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.
Medical subject headings
- Antitubercular Agents
- Histone Code
- Isoniazid
- Isonicotinic Acids