Specific phosphorylation of histone demethylase KDM3A determines target gene expression in response to heat shock.
Specific phosphorylation of histone demethylase KDM3A determines target gene expression in response to heat shock.
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组蛋白去甲基化酶 KDM3A 的特异性磷酸化决定热激响应中的靶基因表达
DOI：
10.1371/journal.pbio.1002026
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发表时间：
2014-12
期刊：
影响因子：
9.8
通讯作者：
Shen YF
中科院分区：
文献类型：
--
作者：
Cheng MB;Zhang Y;Cao CY;Zhang WL;Zhang Y;Shen YF
热应激下组蛋白去甲基化酶KDM3A的磷酸化使其能够被信号转导及转录激活因子1（Stat1）特异性招募至靶基因。
组蛋白赖氨酸（K）残基可被甲基转移酶和乙酰转移酶修饰，从而以多种方式调控RNA合成。与组蛋白赖氨酸乙酰化普遍具有的激活作用不同，组蛋白赖氨酸甲基化的作用会随添加的甲基数量以及这些甲基在组蛋白尾部的位置而有所不同。组蛋白赖氨酸去甲基化酶（KDMs）可抵消甲基转移酶的活性，并去除组蛋白特定赖氨酸残基上的甲基。KDM3A（也称为JHDM2A或JMJD1A）是一种H3K9me2/1去甲基化酶。KDM3A通过调控其相关基因发挥多种功能，这些基因参与精子发生、代谢和细胞分化过程。然而，KDM3A活性的调控机制在很大程度上仍不明确。在此，我们证实丝裂原和应激激活蛋白激酶1（MSK1）可使KDM3A的丝氨酸264位点发生特异性磷酸化（p - KDM3A），该位点在人类基因组基因座的调控区域富集。在热休克条件下，p - KDM3A与转录因子Stat1直接相互作用并被其招募，以激活p - KDM3A靶基因。热休克细胞中，Stat1结合位点处H3K9me2的去甲基化特别依赖于p - KDM3A的共表达。与热休克不同，干扰素 - γ（IFN - γ）处理不会通过MSK1使KDM3A发生磷酸化，从而消除了其下游效应。据我们所知，这是首个表明KDM可通过磷酸化修饰来决定其在热应激下与靶基因特异性结合的证据。
组蛋白甲基化调控基因表达，若该过程出现缺陷，可能对健康产生严重影响。组蛋白赖氨酸去甲基化酶（KDMs）可抵消甲基转移酶的活性并去除组蛋白上的甲基。KDM3A是一种H3K9me2/1去甲基化酶，通过调控其靶基因发挥多种功能，这些靶基因参与精子发生、代谢和细胞分化。然而，KDM3A在特定时间对特定基因进行调控的潜在机制在很大程度上仍不明确。在此我们发现，一种生理应激——温度升高——可通过MSK1激酶诱导人类细胞中KDM3A发生磷酸化。这种磷酸化形式的KDM3A与转录因子Stat1直接相互作用，使Stat1能够将KDM3A招募至特定靶基因启动子处的Stat1结合序列。随后，KDM3A对这些靶标处的H3K9me2/1进行去甲基化，从而在热应激下引发特定基因的表达。我们得出结论，热休克可通过一种以KDM3A磷酸化为核心的新激活机制影响人类细胞中众多基因的表达。
Phosphorylation of histone demethylase KDM3A in response to thermal stress enables its specific recruitment to target genes by Stat1. Histone lysine (K) residues, which are modified by methyl- and acetyl-transferases, diversely regulate RNA synthesis. Unlike the ubiquitously activating effect of histone K acetylation, the effects of histone K methylation vary with the number of methyl groups added and with the position of these groups in the histone tails. Histone K demethylases (KDMs) counteract the activity of methyl-transferases and remove methyl group(s) from specific K residues in histones. KDM3A (also known as JHDM2A or JMJD1A) is an H3K9me2/1 demethylase. KDM3A performs diverse functions via the regulation of its associated genes, which are involved in spermatogenesis, metabolism, and cell differentiation. However, the mechanism by which the activity of KDM3A is regulated is largely unknown. Here, we demonstrated that mitogen- and stress-activated protein kinase 1 (MSK1) specifically phosphorylates KDM3A at Ser264 (p-KDM3A), which is enriched in the regulatory regions of gene loci in the human genome. p-KDM3A directly interacts with and is recruited by the transcription factor Stat1 to activate p-KDM3A target genes under heat shock conditions. The demethylation of H3K9me2 at the Stat1 binding site specifically depends on the co-expression of p-KDM3A in the heat-shocked cells. In contrast to heat shock, IFN-γ treatment does not phosphorylate KDM3A via MSK1, thereby abrogating its downstream effects. To our knowledge, this is the first evidence that a KDM can be modified via phosphorylation to determine its specific binding to target genes in response to thermal stress. Histone methylation regulates gene expression and can have drastic consequences for health if the process is defective. Histone lysine demethylases (KDMs) counteract the activity of methyl-transferases and remove methyl group(s) from histones. KDM3A is a H3K9me2/1 demethylase that performs diverse functions via the regulation of its target genes, which are involved in spermatogenesis, metabolism, and cell differentiation. However, the mechanisms underlying KDM3A regulation of specific genes at specific times are largely unknown. Here we found that a physiological stress—elevated temperature—induces KDM3A phosphorylation in human cells via the MSK1 kinase. This phosphorylated form of KDM3A directly interacts with the transcription factor Stat1, which enables Stat1 to recruit KDM3A to Stat1-binding sequences at the promoters of specific target genes. KDM3A then acts to demethylate H3K9me2/1 at these targets, thereby causing specific gene expression in response to the thermal stress. We conclude that heat shock can affect the expression of many genes in human cells via a novel activation mechanism that is centered around the phosphorylation of KDM3A.
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影响因子：
4.8
作者：
Li, Zhao-yong;Yang, Jun;Shen, Yu-fei
通讯作者：
Shen, Yu-fei
DOI：
10.1016/s1357-2725(02)00197-8
发表时间：
2003-03-01
影响因子：
4
作者：
Liu, BS;Wang, N;Shen, YF
通讯作者：
Shen, YF
DOI：
10.1073/pnas.51.5.786
发表时间：
1964-01-01
影响因子：
11.1
作者：
ALLFREY, VG;FAULKNER, R;MIRSKY, AE
通讯作者：
MIRSKY, AE
影响因子：
16
作者：
Nam, Hye Jin;Boo, Kyungjin;Baek, Sung Hee
通讯作者：
Baek, Sung Hee
影响因子：
64.5
作者：
Murayama, Akiko;Ohmori, Kazuji;Yanagisawa, Junn
通讯作者：
Yanagisawa, Junn