HIC1 epigenetically represses CIITA transcription in B lymphocytes
HIC1 epigenetically represses CIITA transcription in B lymphocytes
复制标题
HIC1 表观遗传抑制 B 淋巴细胞中的 CIITA 转录
DOI：
10.1016/j.bbagrm.2016.10.003
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发表时间：
2016
影响因子：
4.7
通讯作者：
Xu Yong
中科院分区：
文献类型：
--
作者：
Zeng Sheng;Yang Yuyu;Cheng Xian;Zhou Bisheng;Li Ping;Zhao Yuhao;Kong Xiaocen;Xu Yong
B淋巴细胞分化为同位素特异性浆细胞是适应性免疫中的一个标志性事件。在B细胞成熟过程中，II类反式激活因子(CIITA)基因的表达下调，尽管其潜在的表观遗传机制尚未完全明确。在这里，我们报告了癌症中高甲基化1(HIC1)在分化的B淋巴细胞中上调，与CIITA抑制平行。HIC1的过表达直接抑制了B细胞的内源性CIITA转录。报告实验和染色质免疫沉淀(ChIP)实验证实，HIC1与CIITAIII型启动子(−-545/−-113)结合；该区域保守的HIC1位点突变后，CIITA反式抑制作用被取消。更重要的是，去除HIC1和小干扰RNA(SiRNA)可以恢复分化B细胞中CIITA的表达。在机制上，HIC1优先与CIITA启动子相互作用，并将DNMT1和DNMT3b募集到启动子中，协同抑制CIITA转录。相反，沉默DNMT1/DNMT3b或用5-aza-DC抑制DNMT活性可减弱CIITA的反式抑制作用。因此，我们的数据证实HIC1是一个新的参与B细胞分化的因子，作为CIITA转录的表观遗传抑制因子。
Differentiation of B lymphocytes into isotope-specific plasma cells represents a hallmark event in adaptive immunity. During B cell maturation, expression of the class II transactivator (CIITA) gene is down-regulated although the underlying epigenetic mechanism is not completely defined. Here we report that hypermethylated in cancer 1 (HIC1) was up-regulated in differentiating B lymphocytes paralleling CIITA repression. Over-expression of HIC1 directly repressed endogenous CIITA transcription in B cells. Reporter assay and chromatin immunoprecipitation (ChIP) assay confirmed that HIC1 bound to the proximal CIITA type III promoter (− 545/− 113); mutation of a conserved HIC1 site within this region abrogated CIITA trans-repression. More important, depletion of HIC1 with small interfering RNA (siRNA) restored CIITA expression in differentiating B cells. Mechanistically, HIC1 preferentially interacted with and recruited DNMT1 and DNMT3b to the CIITA promoter to synergistically repress CIITA transcription. On the contrary, silencing of DNMT1/DNMT3b or inhibition of DNMT activity with 5-aza-dC attenuated CIITA trans-repression. Therefore, our data identify HIC1 as a novel factor involved in B cell differentiation acting as an epigenetic repressor of CIITA transcription.