From Beads on a String to the Pearls of Regulation: the Structure and Dynamics of Chromatin 341 H1 and HMGB1: modulators of chromatin structure

Histone H1 and HMGB1 (high-mobility group protein B1) are the most abundant chromosomal proteins apart from the core histones (on average, one copy per nucleosome and per ten nucleosomes respectively). They are both highly mobile in the cell nucleus, with high on/off rates for binding. In vivo and in vitro evidence shows that both are able to organize chromatin structure, with H1 binding resulting in amore stable structure and HMGB1 binding in a less stable structure. The binding sites for H1 and HMGB1 in chromatin are partially overlapping, and replacement of H1 by HMGB1 through the highly dynamic nature of their binding, possibly facilitated by interaction between them, could result in switching of chromatin states. Binding of HMGB1 to DNA or chromatin is regulated by its long and highly acidic tail, which is also involved in H1 binding. The present article focuses mainly on HMGB1 and its interaction with chromatin and H1, as well as its chaperone role in the binding of certain transcription factors (e.g. p53) to their cognate DNA. Introduction Histone H1 and HMGB1 (high-mobility group protein B1) are considered together in the present paper because these two structurally unrelated proteins, whose modes of binding to chromatin are completely different, may be functionally linked and act in opposition with respect to the stability of chromatin structure. The linker histone (H1) family of proteins are intrinsic chromatin proteins and bind with a stoichiometry of approximately one copy per nucleosome on average [1]; they are approximately 10 times more abundant than HMGB1 and HMGB2, much less mobile [2] and bind to chromatin with higher affinity. H1 has a central folded globular (G) domain, which binds at the nucleosome dyad [3] and stabilizes nucleosome structure, flanked by a basic N-terminal tail and a much longer, highly basic, C-terminal tail, which organizes and neutralizes internucleosomal linker DNA [4,5]. H1 is required for the formation of stable wellordered higher-order chromatin structure [6]. In contrast with H1, HMGB1 and the closely related HMGB2 have been implicated in a variety of DNA transactions in which chromatin structure might need to be loosened in some way and/or in which the DNA is distorted. These include transcription, replication, recombination and DNA repair [7–9]. In the present paper, we focus mainly on HMGB1 and its properties and interactions in the nucleus of higher eukaryotes. The recent explosion of interest in HMGB1 as a non-nuclear/secreted pro-inflammatory cytokine, with RAGE (receptor for advanced glycation end-products) among its targets (reviewed in [10]), will not be discussed. A distinguishing property of HMGB1 in the nucleus is sequence-independent DNA binding and bending, and its