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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.

2021-08-20 | PXD025490 | Pride

Lysine benzoylation is a novel histone mark [ChIP-seq]

Project description:We identified and characterized a previously undescribed histone mark, lysine benzoylation. This histone mark could be modulated by sodium benzoate (SB), an FDA-approved drug and a widely used chemical food preservative, via generation of benzoyl CoA. By ChIP-seq and RNA-seq analysis, we demonstrate that histone lysine benzoylation marks are involved in regulation of gene expression and associated with diverse biological processes. This study therefore reveals a new type of physiological relevant histone mark and identifies non-conical functions of a widely used chemical food preservative.

2018-06-08 | GSE108468 | GEO

Lysine benzoylation is a novel histone mark [RNA-seq]

2018-06-08 | GSE108469 | GEO

Proteomics of Mycobacterium tuberculosis Beijing genotype after acquisition of Isoniazid resistance

Project description:This project provides the first characterization of protein differences in clinical isolates of Mtb after acquisition of resistance to isoniazid (INH), one of the most important drug treatment options against TB. This study determines the global protein differences in a clinical isogenic pair of Mtb, comparing INH susceptibility versus INH resistance.

2016-03-14 | PXD002986 | Pride

Examining the basis of isoniazid tolerance in nonreplicating Mycobacterium tuberculosis using transcriptional profiling

Project description:Background: Understanding how growth state influences Mycobacterium tuberculosis responses to antibiotic exposure provides a window into drug action during patient chemotherapy. In this article, we describe the transcriptional programs mediated by isoniazid (INH) during the transition from log-phase to nonreplicating bacilli, from INH-sensitive to INH-tolerant bacilli respectively, using the Wayne model. Results: INH treatment did not elicit a transcriptional response from nonreplicating bacteria under microarophilic conditions (NRP2), unlike the induction of a robust and well-characterized INH signature in log-phase bacilli. Conclusion: The differential regulation (between drug-free NRP2 and log-phase bacilli) of genes directly implicated in INH resistance could not account for the abrogation of INH killing in nongrowing bacilli. Thus, factors affecting the requirement for mycolic acids and the redox status of bacilli are likely responsible for the reduction in INH efficacy. We speculate on additional mechanisms revealed by transcriptome analysis that might account for INH tolerance. Data is also available from <ahref=http://bugs.sgul.ac.uk/E-BUGS-104 target=_blank>BuG@Sbase</a>

2011-01-17 | E-BUGS-104 | biostudies-arrayexpress

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

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

| PRJNA707505 | ENA

Lysine benzoylation is a novel histone mark

Project description:Lysine benzoylation is a novel histone mark

| PRJNA427334 | ENA

Protein profile at different cellular fractions of Mycobacterium tuberculosis strains after exposure to Isoniazid

Project description:Out of the 10 million of tuberculosis (TB) cases estimated in the world, around 14% are isoniazid (INH) resistant among new cases and 29% among previously treated cases in the last decade. INH is one of the oldest but also one of the more potent drugs to eliminate Mycobacterium tuberculosis (Mtb), the causing agent of TB. Because of the efficiency of isoniazid (INH) against Mycobacterium tuberculosis (Mtb), many studies are still focused in better understand its role in different bacterial metabolic pathways. We recently conducted a study that evaluated the changes in the protein abundance at different cellular fractions when clonal strains of Mtb developed INH resistance in the clinical and laboratory setting. Here, we want to establish which of the protein changes occurred or started because of the initial exposure to INH. Additionally, we wanted to evaluate if those changes happen differently in strains that are sensitive or resistant to INH, evaluating different cellular compartments from two different genetic lineages of Mtb. For this purpose, we analyzed the proteome of each cellular compartment (cytosol, cell wall, membrane and secreted proteins) through liquid chromatography (nano-HPLC) coupled to mass spectrometry using the Orbitrap Velos instrument and a t-test to perform the statistical analysis for each pair comparison.

2019-06-17 | PXD007588 | Pride

Comprehensive biochemical characterization of Mycobacterium tuberculosis clonal strains after isoniazid resistance

Project description:This project describes the isoniazid (INH) resistance acquisition event in Mycobacterium tuberculosis (Mtb) from the proteomics perspective. In this way, an exploration of the protein differences, comparing clonal INH susceptible (INHs) and INHr pairs of Mtb were evaluated. One clonal clinical and one clonal laboratory-derived Mtb pair with different susceptibility profiles to INH were studied. The laboratory INHr strain had one katG mutation (V1A), while the clinical INHr strain had two (V1A and E3V). Large-scale bacterial cultures were grown in triplicate to obtain secreted proteins as well as proteins from cell fractions. The resulting peptide solutions from all fractions were analyzed using liquid-chromatography coupled with tandem mass spectrometry (LC-MS/MS). LC-MS/MS spectra were compared against an Mtb database to determine the protein abundance. Protein abundance differences were tested by Student’s t test. Looking at the same cellular fractions, there were 25 commonly altered Mtb proteins after acquiring INH resistance. These proteins were involved in ATP synthase machinery, lipid metabolism, regulatory events, virulence, detoxification and adaptation processes.

2018-06-25 | PXD009549 | Pride

Lysine benzoylation is a novel histone mark [RNA-seq]

Project description:Lysine benzoylation is a novel histone mark [RNA-seq]

| PRJNA427337 | ENA