Regulation of the high affinity IgE receptor β-chain gene expression

高亲和力的Ig E受体(FcεRI)在触发Ig E介导的变态反应中起关键作用。FcεRI由三个不同的亚基组成，其中β链同时调节FcεRI的细胞内信号和细胞表面的表达。我们先前报道，转录因子β-1通过形成包括FHL3在内的高分子量复合体，通过第四内含子中的一个元件抑制Fc MZF-1链基因的表达。在本研究中，我们首先筛选了与MZF-1和FHL3形成三元复合体的人cDNA文库，以鉴定与MZF-1和FHL3结合的大型调控复合体的成分。NFY被认为是与组蛋白脱乙酰酶(HDAC)结合的候选基因，芯片分析表明它与β链基因的第四内含子相互作用。此外，已报道的与NFY结合的HDAC与β链基因的第四内含子区域相互作用。在人肥大细胞系HMC-1经GM-CSF培养后，与β链基因第四内含子区域相互作用的组蛋白的β-Chaingene表达和乙酰化水平均降低。综上所述，这些结果表明，通过第四内含子的元件被MZF1/FHL3/NFY招募到β链基因的HDAC在GM-CSF存在下通过组蛋白的脱乙酰基抑制了β链基因的转录。这些机制不仅涉及细胞类型特异性地抑制β链基因在造血细胞分化过程中的表达，还涉及在特定情况下抑制外周细胞中b链基因的表达。

The high affinity IgE receptor (FcεRI) plays a key role in triggering IgE-mediated allergic reaction. FcεRI consists of three different subunits, of which the β-chain regulates both intracellular signals and cell surface expression of FcεRI.We previously reported that the transcription factor MZF-1 repressed the β-chain gene expression through an element in the fourth intron by forming a high molecular weight complex including FHL3. It was also revealed that GM-CSF induced nuclear translocation of FHL3 in addition to upregulation of MZF-1.In this study, we at first screened a human cDNA library for proteins forming a ternary complex with MZF-1 and FHL3 to identify the constituents of the large regulatory complex binding to the element in the fourth intron. NFY which was reported to bind histone deacetylases (HDACs) was identified as candidate and was shown to interact with the fourth intron region of β-chain gene by a ChIP assay. Furthermore, HDACs which were reported to bind NFY was demonstrated to interact with the fourth intron region of β-chain gene. In a human mast cell line HMC-1cultured with GM-CSF, both β-chaingene expression and acetylation of histones interacting with the fourth intron region of β-chain gene was decreased. Collectively, these results indicated that HDACs, which were recruited to β-chain gene through the element in the fourth intron by MZF-1/FHL3/NFY, repressed β-chain gene transcription by deacetylation of histones in the presence of GM-CSF. These mechanisms will be involved in not only the cell type-specific repression of β-chain gene expression in differentiating hematopoietic cells but also the repression of b-chain gene expression in the peripheral cells under specific circumstances.