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

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

PROVIDER: PRJNA707505 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13890622_1.fastq.gz	Fastqsanger.gz
	SRR13890622_2.fastq.gz	Fastqsanger.gz
	SRR13890623_1.fastq.gz	Fastqsanger.gz
	SRR13890623_2.fastq.gz	Fastqsanger.gz
	SRR13890624_1.fastq.gz	Fastqsanger.gz

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

Project description: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.

2021-08-11 | GSE168473 | GEO

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

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

Project description: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.

| S-EPMC8452692 | biostudies-literature

Gene expression profile of wild-type and isoniazid resistant strains of Mycobacterium smegmatis

Project description:Understanding emergence of drug resistance in pathogens systematically is a major challenge. To address this issue, lab-evolved strain resistant to first-line tuberculosis drug, isoniazid (INH), was analysed. Transcriptome analysis of different conditions revealed genes that are differentially regulated in wild-type (WT) and isoniazid resistant (2XR and 4XR) strains. Microarray analysis was performed for WT, sub-MIC, 2XR and 4XR strains of Mycobacterium smegmatis. Overall, the numbers of DEGs observed are 1529 in sub-MIC (596 - up, 933 - down), 1381 (899 – up, 482 – down) in 2XR and 716 in 4XR (267 – up, 449 – down) conditions. 52 of them are seen to be up-regulated across all drug concentrations as compared to WT while 185 are seen to be down-regulated in all. Transcriptome analysis revealed that there are variations in gene expression pattern in the resistant strains as compared to WT strain. This indicates that differential regulation of genes is, in some way, responsible for conferring the phenotype to the organism.

2014-12-13 | GSE64132 | GEO

Small RNAs in anti-tuberculosis drug-induced liver injury

Project description:The antimicrobials isoniazid and pyrazinamide, used for the treatment of tuberculosis are known to cause drug-induced liver injury in humans. This limits the effectiveness of tuberculosis treatment, resulting in incomplete cure, relapse and the development of antimicrobial resistance. MicroRNAs are known to be good biomarkers of disease, with the microRNA miR-122 being diagnostic for liver injury. In this study zebrafish larvae were exposed to the anti-tuberculosis drugs isoniazid and pyrazinamide at concentrations which demonstrated liver injury by microscopy and histology. The aim of this study is to understand small RNA changes occurring in anti-tuberculosis drug-induced liver injury and to attempt to identify novel microRNA biomarkers of liver injury.

2023-12-25 | GSE146260 | GEO

Mycobacterium tuberculosis transcriptional response to Isoniazid

Project description:The ability of Mycobacterium tuberculosis (Mtb) to adopt heterogeneous physiological states, underlies it’s success in evading the immune system and tolerating antibiotic killing. Drug tolerant phenotypes are a major reason why the tuberculosis (TB) mortality rate is so high, with over 1.8 million deaths annually. To develop new TB therapeutics that better treat the infection (faster and more completely), a systems-level approach is needed to reveal the complexity of network-based adaptations of Mtb. Here, we report the transcriptional response of Mtb to the drug isoniazid. We performed transcriptomic sequencing (RNA-seq) on Mtb bacilli at 4, 24, 72 h following exposure to the drug.

2021-12-15 | GSE165581 | 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

Expression profiling of extensively drug-resistant tuberculosis isolates and H37Rv exposed to anti-TB compounds

2014-01-07 | GSE53843 | GEO

Expression profiling of extensively drug-resistant tuberculosis isolates and H37Rv exposed to anti-TB compounds

Project description:To explore the mechanism of drug resistance, most works focused on resistance associated genetic mutations, whereas concerns for resistance related gene expression are relatively low. Here a global expression analysis was performed between a reference strain H37Rv and two clinical extensively drug-resistant (XDR) strains with three anti-TB drug exposures {isoniazid (INH), capreomycin (CAP), rifampicin (RIF)} Strains were grown in Middlebrook 7H9 broth supplemented with ADC, 0.05% Tween 80 and 0.2% glycerol to an OD600 of 0.5-0.6, and then respectively treated with control (water), 10×MIC INH, 1×MIC RIF and CAP for 6hr.

2014-01-07 | E-GEOD-53843 | biostudies-arrayexpress

Effect of addition of cysteine to isoniazid treatment of Mycobacterium tuberculosis

Project description:Transcriptional profiling of Mycobacterium tuberculosis H37Rv after 4 hours of combination isoniazid and cysteine treatment relative to treatment with isoniazid alone.

2017-03-27 | GSE86184 | GEO

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