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Identification And Characterization Of Histone Mark Isonicotinylation That Is Induced By Anti-tuberculosis First-line Drug Isoniazid

ABSTRACT: We identified and characterized a previously undescribed histone mark, lysine isonicotinylation. This histone mark could be modulated by isoniazid (INH), aa preferred and widely used drug for the treatment of latent tuberculosis (TB), via generation of isonicotyl CoA. By RNA-seq analysis, we demonstrate that histone lysine isonicotinylation marks are involved in regulation of gene expression and associated with diverse biological processes. Thereby,enhanced isonicotinylation may represent a mechanism underlying side effects in patients who taking long-term isoniazid and may also increase risk for cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE168473 | GEO | 2021/08/11

REPOSITORIES: GEO

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

Project description:Isoniazid (INH) is the first-line anti-tuberculosis drug used for nearly seventy years. Metabolites of INH showed hepatotoxicity in human and tumorigenicity in rodents. However, mechanism underlying the side effects of INH is elusive. Histone acylation is known to be modulated by intracellular metabolites. Here, we report INH and its metabolites induces a novel post-translational modification (PTM) on histones, the lysine isonicotinylation (Kinic), also called 4-picolinylation, in cells and mice. INH functions as a donor to promote biosynthesis of isonicotinyl-CoA that is used for a co-factor of intracellular isonicotinylation reaction. Twenty-six isonicotinylation sites were identified on histones in HepG2 cells by mass spectrometry. Acetyltransferases CREB-binding protein (CBP) and P300 were found to catalyze histone Kinic, whilst histone deacetylase HDAC3 functions as a deisonicotinylase. MNase sensitivity assay and RNA-seq analysis showed that histone Kinic relaxes chromatin structure and promotes gene transcription. Importantly, INH-mediated histone Kinic upregulates PIK3R1 gene expression and activates PI3K/Akt/mTOR signaling pathway in liver cancer cells, linking INH to the tumorigenicity in liver. Further, Kinic was found increased in liver cancer patients with concomitant raised PIK3R1 protein level. In addition, histone Kinic also affects TNF and GABAergic synapse signaling pathways that are closely related to INH-caused side effects. Taken together, we demonstrated that lysine isonicotinylation represents the first histone acylation mark with the pyridine ring that may arise broad biological effects. Therefore, INH-induced isonicotinylation is likely a mechanism accounting for side effects in patients who taking long-term INH for anti-tuberculosis therapy and this modification may also increase cancer risk in human.

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Identification And Characterization Of Histone Mark Isonicotinylation That Is Induced By Anti-tuberculosis First-line Drug Isoniazid

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