Multifunctionality of the linker histones: an emerging role for protein-protein interactions

Abstract

Linker histones, e.g., H1, are best known for their ability to bind to nucleosomes and stabilize both nucleosome structure and condensed higher-order chromatin structures. However, over the years many investigators have reported specific interactions between linker histones and proteins involved in important cellular processes. The purpose of this review is to highlight evidence indicating an important alternative mode of action for H1, namely protein-protein interactions. We first review key aspects of the traditional view of linker histone action, including the importance of the H1 C-terminal domain. We then discuss the current state of knowledge of linker histone interactions with other proteins, and, where possible, highlight the mechanism of linker histone-mediated protein-protein interactions. Taken together, the data suggest a combinatorial role for the linker histones, functioning both as primary chromatin architectural proteins and simultaneously as recruitment hubs for proteins involved in accessing and modifying the chromatin fiber. Nucleosomes and nucleosomal arraysChromosomal DNA is compacted by, and made accessible through, hierarchical levels of ordered chromatin condensation and decondensation. Chromatin is a dynamic nucleoprotein structure formed from histone proteins, DNA, and numerous chromatin-associated proteins. Nucleosomes, the fundamental building blocks of chromatin, are made up of ~150 base pairs (bp) of DNA and an octamer of core histone proteins [1]. The histone octamer consists of two molecules each of histones H2A, H2B, H3, and H4 [2], and is stabile only when wrapped by nucleosomal DNA, or under high-salt solution conditions in vitro [3,4]. Approximately 1.65 superhelical turns of nucleosomal DNA are wrapped around the histone octamer to form the nucleosome, resulting in the first level of DNA condensation. The nucleosome is stabilized by extensive charge-dipole interactions between the main chains of the histones and DNA phosphates, and by hydrogen bonding between the many histone arginine residues inserted into the minor grooves of the DNA [5]. The canonical alpha-helical histone-fold motifs of the core histones ( Figure 1A) bind nucleosomal DNA and make up the structured core of the nucleosome, while the N-terminal "tail" domains (NTDs) pass outside the gyres of the DNA and extend beyond the nucleosome core structure [6]. The NTDs are between 14 and 38 amino acids in length, highly basic (enriched in lysine and arginine residues), and are largely devoid of regular secondary structure [7]. The NTDs and the histone-fold domains [8] are sites of numerous, combinatorial posttranslational modifications that influence the accessibility of the nucleosomes to chromatin-associated proteins, transcription factors, and other regulatory proteins, and regulate chromatin condensation (for reviews, see [9-11]). A polymer of nucleosomes assembled on a single DNA molecule is known as a nucleosomal array. The nucleosomes in a nucleosomal array are connected by core histone-free, extra-nucleosoma...

H1 linker histone promotes epigenetic silencing by regulating both DNA methylation and histone H3 methylation

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