Alternate activation of two divergently transcribed mouse genes from a bidirectional promoter is linked to changes in histone modification
Alternate activation of two divergently transcribed mouse genes from a bidirectional promoter is linked to changes in histone modification
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DOI：
10.1074/jbc.m204843200
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发表时间：
2003-01-17
影响因子：
4.8
通讯作者：
Seiser, C
中科院分区：
文献类型：
--
作者：
Schuettengruber, B;Doetzlhofer, A;Seiser, C
胸苷激酶（TK）是一种生长因子诱导的酶，在增殖的哺乳动物细胞中高度表达。小鼠TK mRNA的表达受转录和转录后机制（包括反义转录）的调控。在这里，我们报告了一个从双向TK启动子分歧转录的新基因的鉴定。该基因编码犬尿氨酸甲酰胺酶（KF），一种色氨酸代谢酶。尽管TK基因在白细胞介素-2介导的静息T细胞活化后被诱导，但KF基因同时被抑制。TK启动子受E2 F、SP1、组蛋白乙酰转移酶和脱乙酰酶调节。生长调节转录因子E2 F的结合位点有利于TK启动子活性，但不是KF表达所必需的。相反，SP1结合位点对两个方向的转录都至关重要。组蛋白去乙酰化酶的抑制作用通过抑制素A导致TK/KF启动子处的组蛋白乙酰化增加，从而选择性激活TK启动子并同时关闭KF表达。类似地，TK基因由白细胞介素-2激活与组蛋白乙酰化过度相关，而KF表达与组蛋白乙酰化减少相关。KF基因是哺乳动物基因的罕见例子，其表达与其启动子处的组蛋白低乙酰化有关。
Thymidine kinase (TK) is a growth factor-inducible enzyme that is highly expressed in proliferating mammalian cells. Expression of mouse TK mRNA is controlled by transcriptional and posttranscriptional mechanisms including antisense transcription. Here we report the identification of a novel gene that is divergently transcribed from the bidirectional TK promoter. This gene encodes kynurenine formamidase (KF), an enzyme of the tryptophan metabolism. Whereas the TK gene is induced upon interleukin-2-mediated activation of resting T cells, the KF gene becomes simultaneously repressed. The TK promoter is regulated by E2F, SP1, histone acetyltransferases, and deacetylases. The binding site for the growth-regulated transcription factor E2F is beneficial for TK promoter activity but not required for KF expression. In contrast, the SP1 binding site is crucial for transcription in both directions. Inhibition of histone deacetylases by trichostatin A leads to increased histone acetylation at the TK/KF promoter and thereby to selective activation of the TK promoter and simultaneous shut-off of KF expression. Similarly, TK gene activation by interleukin-2 is linked to histone hyperacetylation, whereas KF expression correlates with reduced histone acetylation. The KF gene is the rare example of a mammalian gene whose expression is linked to histone hypoacetylation at its promoter.