PXD025490

PXD025490 is an original dataset announced via ProteomeXchange.

Title	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
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.
HostingRepository	PRIDE
AnnounceDate	2021-08-20
AnnouncementXML	Submission_2021-08-19_19:52:50.031.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Yuhan Jiang
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	protein modification
Instrument	Orbitrap Fusion Lumos; Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2021-04-20 02:16:48	ID requested
⏵ 1	2021-08-19 19:52:50	announced

Dataset with its publication pending

submitter keyword: histone isonicotinylation, histone isonicotinyltransferases, histone deisonicotinylases, chromatin structure, gene transcription

Hongquan Zhang
contact affiliation	Program for Cancer and Cell Biology, Department of Human Anatomy, Histology and Embryology, and PKU International Cancer Institute, Peking University Health Science Center, #38 Xue Yuan Road, Beijing 100191, China.
contact email	hongquan.zhang@bjmu.edu.cn
lab head
Yuhan Jiang
contact affiliation	Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, P.R. China
contact email	jiangyuhan@bjmu.edu.cn
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD025490
     1. Label: PRIDE project
     2. Name: 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