Norwood Laura E, Grade Stephanie K, Cryderman Diane E, Hines Karrie A, Furiasse Nicholas, Toro Rafael, Li Yuhong, Dhasarathy Archana, Kladde Michael P, Hendrix Mary J C, Kirschmann Dawn A, Wallrath Lori L
The Department of Biochemistry, The University of Iowa, 3136 MERF, Iowa City, IA 52242, USA.
Gene. 2004 Jul 7;336(1):37-46. doi: 10.1016/j.gene.2004.04.003.
Heterochromatin protein 1 Hsalpha (HP1(Hsalpha)) is one of three human proteins that share sequence similarity with Drosophila HP1. HP1 proteins are enriched at centric heterochromatin and play a role in chromatin packaging and gene regulation. In humans, HP1(Hsalpha) is down-regulated in highly invasive/metastatic breast cancer cells, compared to poorly invasive/non-metastatic breast cancer cells. To gain insight into this differential regulation, we have cloned the HP1(Hsalpha) gene and characterized its genomic region. HP1(Hsalpha) is located on human chromosome 12q13.13, 589 bp upstream of the divergently transcribed hnRNPA1 gene. Analysis of the promoter region revealed that differential regulation of HP1(Hsalpha) between the two types of breast cancer cells is lost upon mutation of an USF/c-myc transcription factor binding site located 172 bp upstream of the predicted HP1(Hsalpha) transcription start site. These findings provide insights into the down-regulation of HP1(Hsalpha) in highly invasive/metastatic breast cancer cells. To examine the functional properties of HP1(Hsalpha), experiments were performed using Drosophila melanogaster as a genetic system. When human HP1(Hsalpha) was expressed in transgenic Drosophila, silencing of reporter genes inserted at centric and telomeric locations was enhanced. Furthermore, expression of HP1(Hsalpha) rescued the lethality of homozygous Su(var)2-5 mutants lacking HP1. Taken together, these results demonstrate the participation of HP1(Hsalpha) in silent chromatin formation and that HP1(Hsalpha) is a functional homologue of Drosophila HP1.
异染色质蛋白1 Hsα（HP1（Hsα））是三种与果蝇HP1具有序列相似性的人类蛋白质之一。HP1蛋白在着丝粒异染色质中富集，并在染色质包装和基因调控中发挥作用。在人类中，与低侵袭性/非转移性乳腺癌细胞相比，HP1（Hsα）在高侵袭性/转移性乳腺癌细胞中表达下调。为了深入了解这种差异调控，我们克隆了HP1（Hsα）基因并对其基因组区域进行了表征。HP1（Hsα）位于人类染色体12q13.13，在反向转录的hnRNPA1基因上游589 bp处。对启动子区域的分析表明，在预测的HP1（Hsα）转录起始位点上游172 bp处的USF/c-myc转录因子结合位点发生突变后，两种类型乳腺癌细胞之间HP1（Hsα）的差异调控消失。这些发现为高侵袭性/转移性乳腺癌细胞中HP1（Hsα）的下调提供了见解。为了研究HP1（Hsα）的功能特性，使用黑腹果蝇作为遗传系统进行了实验。当人类HP1（Hsα）在转基因果蝇中表达时，插入着丝粒和端粒位置的报告基因的沉默增强。此外，HP1（Hsα）的表达挽救了缺乏HP1的纯合子Su（var）2-5突变体的致死性。综上所述，这些结果证明了HP1（Hsα）参与沉默染色质的形成，并且HP1（Hsα）是果蝇HP1的功能同源物。
