Abstract 260: Identification of the role of linker histone H1 in estrogen receptor binding and activity

Abstract

Abstract The activity of estrogen receptor (ER) in the nucleus is a highly dynamic process, which is tightly regulated by many factors. Among the molecules proposed to facilitate ER activity are proteasome components, chromatin-remodeling complexes, heat shock proteins and histones. Particularly the linker histone H1 seems important, as it is essential to the stability of the higher-order chromatin structure and has been associated with the regulation of gene expression for many years. Eleven linker histones have been identified in humans to date, differing in their timing of expression, extent of post-translational modification and affinity to DNA in chromatin. However, their exact function and ability to differentially affect gene expression are not as clearly understood. It seems probable that linker histones need to be removed, reduced in amount or somehow modified during transcription in order to allow access to the transcription machinery and that these processes are different for the different linker histone subtypes. Here we show that removal of linker histone H1 is a prerequisite for the full activation of ER-regulated target genes in ER positive breast cancer cells. This process is mediated through the activity of the cyclin-dependent kinase 2 (CDK2), which phosphorylates H1 in a hormone-dependent manner, and thereby loosens the interaction of the linker histone with DNA in chromatin. The extent of phosphorylation differs significantly between the different subtypes, suggesting a differential involvement of the H1s in ER-mediated gene expression. Collectively, our results show that H1 dissociation is required for ER-mediated gene expression in breast cancer and that the H1 subtypes may play distinct functional roles in the transcriptional regulation of ER target genes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 260. doi:10.1158/1538-7445.AM2011-260