Kitagawa Hirochika, Fujiki Ryoji, Yoshimura Kimihiro, Mezaki Yoshihiro, Uematsu Yoshikatsu, Matsui Daisuke, Ogawa Satoko, Unno Kiyoe, Okubo Mataichi, Tokita Akifumi, Nakagawa Takeya, Ito Takashi, Ishimi Yukio, Nagasawa Hiromichi, Matsumoto Toshio, Yanagisawa Junn, Kato Shigeaki
Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, 113-0032, Tokyo, Japan.
Cell. 2003 Jun 27;113(7):905-17. doi: 10.1016/s0092-8674(03)00436-7.
We identified a human multiprotein complex (WINAC) that directly interacts with the vitamin D receptor (VDR) through the Williams syndrome transcription factor (WSTF). WINAC has ATP-dependent chromatin-remodeling activity and contains both SWI/SNF components and DNA replication-related factors. The latter might explain a WINAC requirement for normal S phase progression. WINAC mediates the recruitment of unliganded VDR to VDR target sites in promoters, while subsequent binding of coregulators requires ligand binding. This recruitment order exemplifies that an interaction of a sequence-specific regulator with a chromatin-remodeling complex can organize nucleosomal arrays at specific local sites in order to make promoters accessible for coregulators. Furthermore, overexpression of WSTF could restore the impaired recruitment of VDR to vitamin D regulated promoters in fibroblasts from Williams syndrome patients. This suggests that WINAC dysfunction contributes to Williams syndrome, which could therefore be considered, at least in part, a chromatin-remodeling factor disease.
我们鉴定出一种人类多蛋白复合物（WINAC），它通过威廉姆斯综合征转录因子（WSTF）直接与维生素D受体（VDR）相互作用。WINAC具有ATP依赖性染色质重塑活性，并且包含SWI/SNF组件和与DNA复制相关的因子。后者可能解释了WINAC对正常S期进程的需求。WINAC介导未结合配体的VDR募集到启动子中的VDR靶位点，而共调节因子的后续结合则需要配体结合。这种募集顺序表明，序列特异性调节因子与染色质重塑复合物的相互作用可以在特定局部位点组织核小体阵列，以使启动子可被共调节因子接近。此外，WSTF的过表达可以恢复威廉姆斯综合征患者成纤维细胞中VDR对维生素D调节启动子的受损募集。这表明WINAC功能障碍导致了威廉姆斯综合征，因此至少部分地可以将其视为一种染色质重塑因子疾病。
