Epigenetic changes and suppression of the nuclear factor of activated T cell 1 (NFATC1) promoter in human lymphomas with defects in immunoreceptor, signaling
Epigenetic changes and suppression of the nuclear factor of activated T cell 1 (NFATC1) promoter in human lymphomas with defects in immunoreceptor, signaling
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DOI：
10.2353/ajpath.2008.070294
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发表时间：
2008-01-01
影响因子：
6
通讯作者：
Serfling, Edgar
中科院分区：
文献类型：
--
作者：
Akimzhanov, Askar;Krenacs, Laszlo;Serfling, Edgar
活化T细胞核因子1（NFATc 1）基因座是小鼠致瘤性逆转录病毒的常见插入位点，表明转录因子NFATc 1在淋巴瘤发生中的作用。虽然NFATc 1在大多数人的初级淋巴细胞和成熟的人类T-和B-细胞肿瘤中表达，但我们通过组织化学染色显示，NFATc 1的表达在间变性大细胞淋巴瘤和经典霍奇金淋巴瘤（HL）中受到抑制。在HL细胞系中，NFATc 1沉默与组蛋白H3乙酰化、H3-K4三甲基化和SO因子结合的减少相关，但与NFATC 1 P1启动子结合的HP 1增加相关。连同我们在所有间变性大细胞淋巴瘤和许多HL系中检测到的NFATC 1 PI启动子的DNA超甲基化，这些观察结果反映了转录沉默的典型迹象。在几个淋巴瘤细胞系中，NFATC 1启动子DNA的甲基化导致了一个“低甲基化窗口”，其两侧是Sp1结合位点。连同HL细胞中NFATC 1 P1启动子处的Sp1表达不足，这表明Sp1因子可以定向方式保护P1 DNA甲基化。阻断免疫受体信号传导导致NFATC 1 P1启动子沉默，并导致H3乙酰化和H3-K4甲基化减少，但不导致DNA甲基化。这表明组蛋白修饰先于NFATC 1启动子沉默中的DNA甲基化。
The nuclear factor of activated T cell 1 (Nfatc1) locus is a common insertion site for murine tumorigenic retroviruses, suggesting a role of transcription factor NFATc1 in lymphomagenesis. Although NFATc1 is expressed in most human primary lymphocytes and mature human T- and B-cell neoplasms, we show by histochemical stainings that NFATc1 expression is suppressed in anaplastic large cell lymphomas and classical Hodgkin's lymphomas (HLs). In HL cell lines, NFATc1 silencing correlated with a decrease in histone H3 acetylation, H3-K4 trimethylation, and SO factor binding but with an increase in HP1 binding to the NFATC1 P1 promoter. Together with DNA hypermethylation of the NFATC1 PI promoter, which we detected in-all anaplastic large cell lymphoma and many HL lines, these observations reflect typical signs of transcriptional silencing. In several lymphoma lines, methylation of NFATC1 promoter DNA resulted in a "window of hypomethylation," which is flanked by Sp1-binding sites. Together with the under-representation of Sp1 at the NFATC1 P1 promoter in HL cells, this suggests that Sp1 factors can protect P1 DNA methylation in a directional manner. Blocking immunoreceptor signaling led to NFATC1 P1 promoter silencing and to a decrease in H3 acetylation and H3-K4 methylation but not DNA methylation. This shows that histone modifications precede the DNA methylation in NFATC1 promoter silencing.