High mobility group protein 1: A collaborator in nucleosome dynamics and estrogen-responsive gene expression

Abstract

High mobility group protein 1 (HMGB1) is a multifunctional protein that interacts with DNA and chromatin to influence the regulation of transcription, DNA replication and repair and recombination. We show that HMGB1 alters the structure and stability of the canonical nucleosome (N) in a nonenzymatic, adenosine triphosphate-independent manner. As a result, the canonical nucleosome is converted to two stable, physically distinct nucleosome conformers. Although estrogen receptor (ER) does not bind to its consensus estrogen response element within a nucleosome, HMGB1 restructures the nucleosome to facilitate strong ER binding. The isolated HMGB1-restructured nucleosomes (N’ and N’’) remain stable and exhibit a number of characteristics that are distinctly different from the canonical nucleosome. These findings complement previous studies that showed (1) HMGB1 stimulates in vivo transcriptional activation at estrogen response elements and (2) knock down of HMGB1 expression by siRNA precipitously reduced transcriptional activation. The findings indicate that a major facet of the mechanism of HMGB1 action involves a restructuring of aspects of the nucleosome that appear to relax structural constraints within the nucleosome. The findings are extended to reveal the differences between ER and the other steroid hormone receptors. A working proposal outlines mechanisms that highlight the multiple facets that HMGB1 may utilize in restructuring the nucleosome.

Keywords: Nucleosome dynamics; Estrogen receptor; High mobility group protein 1; Conformational dynamics; Energy landscape

Core tip: Response elements or target sites for transcription factors in DNA are often found veiled within a nucleosome in a chromatin milieu and in many cases are not accessible. Although the nucleosome/chromatin network is generally repressive to transcription, there are now a number of enzymatic strategies that have now been recognized that remodel the nucleosome to facilitate transcription factor access. We recently showed that estrogen receptor does not bind to a canonical nucleosome. However, we have discovered that high mobility group protein 1 (HMGB1) restructures the nucleosome in a nonenzymatic manner to facilitate strong estrogen receptor binding. This review will provide background for this work and outline our findings, characterize the HMGB1-restructured nucleosomes and propose a working model to account for the HMGB1 restructuring activity.