Han Songyan, Lu Jun, Zhang Yu, Cheng Cao, Han Liping, Wang Xiuli, Li Lin, Liu Chunyan, Huang Baiqu
Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China.
Biochem J. 2006 Dec 15;400(3):439-48. doi: 10.1042/BJ20061085.
The critical role of IL-5 (interleukin-5) in eosinophilic inflammation implicates it as a therapeutic target for allergic diseases. The aim of the present study was to elucidate the molecular basis for the involvement of reversible histone acetylation in IL-5 transcriptional regulation. We provide evidence that HDAC4 (histone deacetylase 4) and p300, a known HAT (histone acetyltransferase), reversibly controlled the activity of the IL-5 promoter in vivo and in vitro, with a concurrent alteration of histone H3 acetylation status at the promoter regions. The nucleo-cytoplasmic shuttling of HDAC4 was shown to play an important role in the suppressive function of HDAC4 in IL-5 gene expression. Point mutation and reporter ChIP (chromatin immunoprecipitation) studies determined that the four transcription factors binding on the IL-5 promoter, i.e. C/EBPbeta (CAAT/enhancer-binding protein beta), GATA3 (GATA binding protein 3), NFAT (nuclear factor of activated T cells) and YY1 (Yin and Yang 1), were essential for the recruitment of HDAC4. Consistent with these observations, HDAC4 was found to form protein complexes with GATA3 and YY1, and to co-exist in the nuclei with GATA3. We propose that the unique regulatory mechanism of IL-5 gene transcription involves the reversible histone modification catalysed by HDAC4 and p300, which are recruited by the transcription factors. The dynamic balance in IL-5 transcriptional regulation is achieved through interactions among HATs/HDACs, histones and transcription factors. These data contribute to understanding the molecular mechanisms of IL-5 regulation, which is crucial to the development of new therapeutic strategies for IL-5-related allergic diseases.
白细胞介素-5（IL-5）在嗜酸性粒细胞炎症中发挥关键作用，这使其成为过敏性疾病的治疗靶点。本研究旨在阐明可逆性组蛋白乙酰化参与IL-5转录调控的分子基础。我们提供的证据表明，组蛋白去乙酰化酶4（HDAC4）和已知的组蛋白乙酰转移酶（HAT）p300在体内和体外可逆地控制IL-5启动子的活性，同时启动子区域的组蛋白H3乙酰化状态也发生改变。HDAC4的核质穿梭在其对IL-5基因表达的抑制功能中起重要作用。点突变和报告基因染色质免疫沉淀（ChIP）研究确定，结合在IL-5启动子上的四种转录因子，即CCAAT/增强子结合蛋白β（C/EBPβ）、GATA结合蛋白3（GATA3）、活化T细胞核因子（NFAT）和阴阳1（YY1），对于HDAC4的募集至关重要。与这些观察结果一致，发现HDAC4与GATA3和YY1形成蛋白复合物，并与GATA3共存于细胞核中。我们提出，IL-5基因转录的独特调控机制涉及由转录因子募集的HDAC4和p300催化的可逆组蛋白修饰。IL-5转录调控中的动态平衡是通过组蛋白乙酰转移酶/组蛋白去乙酰化酶（HATs/HDACs）、组蛋白和转录因子之间的相互作用实现的。这些数据有助于理解IL-5调控的分子机制，这对于开发与IL-5相关的过敏性疾病新治疗策略至关重要。
