Regulation of chromatin structure and function by HMGN proteins

Abstract

High mobility group nucleosome-binding (HMGN) proteins are architectural non-histone chromosomal proteins that bind to nucleosomes and modulate the structure and function of chromatin. The interaction of HMGN proteins with nucleosomes is dynamic and the proteins compete with the linker histone H1 chromatin-binding sites. HMGNs reduce the H1-mediated compaction of the chromatin fiber and facilitate the targeting of regulatory factors to chromatin. They modulate the cellular epigenetic profile, affect gene expression and impact the biological processes such as development and the cellular response to environmental and hormonal signals. Here we review the role of HMGN in chromatin structure, the link between HMGN proteins and histone modifications, and discuss the consequence of this link on nuclear processes and cellular phenotype.

Figure 1. Structural features of the High Mobility Group N (HMGN) proteins

A. Functional domains of the High Mobility Group N (HMGN) proteins. Sequences of the human HMGN proteins are aligned. All HMGN proteins contain four functional domains (shadowed): two Nuclear Localization Signal domains (NLS1 and NLS2, light green), a Nucleosomal Binding Domain (NBD, light purple) and a Regulatory Domain (RD, cyan). The invariant amino-acid residues within NBD domain are named as NBD core (shadowed by brick red) and four residues essential for specific binding to nucleosomes are marked by magenta stars above the core NBD. The RD domain is less conserved and has a net negative charge. The C-terminus of HMGN5 is ~300 amino acids longer than that of the other HMGNs. B. Intrinsically disordered regions (IDRs) in HMGN family proteins. The sequences of human HMGN proteins has been analyzed by PONDR (Predictors of Natural Disordered Regions) - a series of neural network predictors (NNPs) that use amino acid sequence data to predict disorder in a given region [72].Values greater than 0.5 represent intrinsically disorder regions in the protein. C. A graph of intrinsically disordered regions in mouse HMGN5.

Figure 2. A model of HMGN1 modulation of the rate of stress-activated phosphorylation of H3S10 in chromatin of FosB immediate early genes (modified from [49])

A. In quiescent cells, non-phosphorylated HMGN1 is bound to nucleosomes B. Anisomycin or similar stress signals activate MSKs through MAPK signaling pathway. The kinases phosphorylate nuclear targets, including HMGN1. Phosphorylation of HMGN1 at Ser20 and Ser24 abolishes the binding of the protein to nucleosomes, thus shifting the equilibrium towards non-bound phosphorylated HMGN1 C. Phosphorylated HMGN1 leaves nucleosomes, removing the inhibiting activity of HMGN1 upon H3S10 phosphorylation D. Absence of HMGN1 enhances the rate of nucleosomal H3 phosphorylation, and alleviates the rounds of transcription.