Human MI-ER1 alpha and beta function as transcriptional repressors by recruitment of histone deacetylase 1 to their conserved ELM2 domain

mi-er1 (previously called er1) was first isolated from Xenopus laevis embryonic cells as a novel fibroblast growth factor-regulated immediate-early gene. Xmi-er1 was shown to encode a nuclear protein with an N-terminal acidic transcription activation domain. The human orthologue of mi-er1 (hmi-er1) displays 91% similarity to the Xenopus sequence at the amino acid level and was shown to be upregulated in breast carcinoma cell lines and tumors. Alternative splicing at the 3' end of hmi-er1 produces two major isoforms, hMI-ER1alpha and hMI-ER1beta, which contain distinct C-terminal domains. In this study, we investigated the role of hMI-ER1alpha and hMI-ER1beta in the regulation of transcription. Using fusion proteins of hMI-ER1alpha or hMI-ER1beta tethered to the GAL4 DNA binding domain, we show that both isoforms, when recruited to the G5tkCAT minimal promoter, function to repress transcription. We demonstrate that this repressor activity is due to interaction and recruitment of a trichostatin A-sensitive histone deacetylase 1 (HDAC1). Furthermore, deletion analysis revealed that recruitment of HDAC1 to hMI-ER1alpha and hMI-ERIP occurs through their common ELM2 domain. The ELM2 domain was first described in the Caenorhabditis elegans Egl-27 protein and is present in a number of SANT domain-containing transcription factors. This is the first report of a function for the ELM2 domain, highlighting its role in the regulation of transcription.

mi - er1（先前称为er1）最初是从非洲爪蟾胚胎细胞中作为一种新的成纤维细胞生长因子调节的即刻早期基因被分离出来的。已表明Xmi - er1编码一种具有N末端酸性转录激活结构域的核蛋白。mi - er1的人类同源物（hmi - er1）在氨基酸水平上与非洲爪蟾序列显示出91%的相似性，并且已表明在乳腺癌细胞系和肿瘤中上调。hmi - er1的3'端可变剪接产生两种主要异构体，hMI - ER1α和hMI - ER1β，它们包含不同的C末端结构域。在这项研究中，我们研究了hMI - ER1α和hMI - ER1β在转录调控中的作用。利用与GAL4 DNA结合结构域相连的hMI - ER1α或hMI - ER1β融合蛋白，我们表明当这两种异构体被招募到G5tkCAT最小启动子时，都起到抑制转录的作用。我们证明这种抑制活性是由于一种对曲古抑菌素A敏感的组蛋白去乙酰化酶1（HDAC1）的相互作用和招募。此外，缺失分析表明HDAC1被招募到hMI - ER1α和hMI - ER1β是通过它们共有的ELM2结构域发生的。ELM2结构域最初是在秀丽隐杆线虫Egl - 27蛋白中被描述的，并且存在于许多含SANT结构域的转录因子中。这是关于ELM2结构域功能的首次报道，突显了它在转录调控中的作用。