Isonicotinylation is a histone mark induced by the anti-tuberculosis first-line drug isoniazid.
Isonicotinylation is a histone mark induced by the anti-tuberculosis first-line drug isoniazid.
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异烟酰化是抗结核一线药物异烟肼诱导的组蛋白标记
DOI：
10.1038/s41467-021-25867-y
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发表时间：
2021-09-20
影响因子：
16.6
通讯作者：
Zhang H
中科院分区：
文献类型：
--
作者：
Jiang Y;Li Y;Liu C;Zhang L;Lv D;Weng Y;Cheng Z;Chen X;Zhan J;Zhang H
异烟肼 (INH) 是一线抗结核药物，已使用近 70 年。然而，INH 副作用的机制仍然难以捉摸。在此，我们报道 INH 及其代谢物在细胞和小鼠中诱导组蛋白翻译后修饰 (PTM)，即赖氨酸异烟酰化 (Kinic)，也称为 4-吡啶甲酰化。 INH 促进异烟酰辅酶 A (Inic-CoA) 的生物合成，异烟酰辅酶 A 是细胞内异烟酰化的辅助因子。质谱分析揭示了 HepG2 细胞组蛋白中的 26 个动力学位点。乙酰转移酶 CREB 结合蛋白 (CBP) 和 P300 催化组蛋白 Kinic，而组蛋白脱乙酰酶 HDAC3 则充当脱异烟碱酶。值得注意的是，MNase 敏感性测定和 RNA-seq 分析表明组蛋白 Kinic 可以松弛染色质结构并促进基因转录。 INH 介导的组蛋白 Kinic 上调 PIK3R1 基因表达并激活肝癌细胞中的 PI3K/Akt/mTOR 信号通路，将 INH 与肝脏致瘤性联系起来。我们证明 Kinici 是一个带有吡啶环的组蛋白酰化标记，可能具有广泛的生物学效应。因此，INH诱导的异烟碱化可能是长期服用INH抗结核治疗的患者产生副作用的原因，并且这种修饰可能会增加人类患癌症的风险。
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 Kinicsites 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 Kinicrelaxes chromatin structure and promotes gene transcription. INH-mediated histone KinicupregulatesPIK3R1gene expression and activates the PI3K/Akt/mTOR signalling pathway in liver cancer cells, linking INH to tumourigenicity in the liver. We demonstrate that Kinicis 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.
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影响因子：
64.8
作者：
Lasko LM;Jakob CG;Edalji RP;Qiu W;Montgomery D;Digiammarino EL;Hansen TM;Risi RM;Frey R;Manaves V;Shaw B;Algire M;Hessler P;Lam LT;Uziel T;Faivre E;Ferguson D;Buchanan FG;Martin RL;Torrent M;Chiang GG;Karukurichi K;Langston JW;Weinert BT;Choudhary C;de Vries P;Van Drie JH;McElligott D;Kesicki E;Marmorstein R;Sun C;Cole PA;Rosenberg SH;Michaelides MR;Lai A;Bromberg KD
通讯作者：
Bromberg KD
影响因子：
5.8
作者：
Liyasova, Mariya S.;Schopfer, Lawrence M.;Lockridge, Oksana
通讯作者：
Lockridge, Oksana
PIK3R1过度表达促进肝细胞癌进展
影响因子：
6.7
作者：
Ai X;Xiang L;Huang Z;Zhou S;Zhang S;Zhang T;Jiang T
通讯作者：
Jiang T
影响因子：
16
作者：
Sabari BR;Tang Z;Huang H;Yong-Gonzalez V;Molina H;Kong HE;Dai L;Shimada M;Cross JR;Zhao Y;Roeder RG;Allis CD
通讯作者：
Allis CD
影响因子：
4.1
作者：
Hall RG;Leff RD;Gumbo T
通讯作者：
Gumbo T