Emerging roles of linker histones in regulating chromatin structure and function

Key Points Studies using X-ray crystallography, NMR and cryo-electron microscopy (cryo-EM) reveal that linker histones (H1) bind to nucleosomes via electrostatic interactions and that this binding can occur in either on-dyad or off-dyad mode. These different binding modes can lead to differential folding of nucleosome arrays, with different levels of compaction. Cryo-EM studies reveal that 30 nm nucleosome arrays form a twisted double helix with the tetra-nucleosome as the structural unit, in which human linker histone variant H1.4 binds off the nucleosome dyad. Folding of the nucleosome array may potentially affect the binding mode of the linker histone. There is evidence that in vivo chromatin fibres in the presence of linker histones are formed by heterogeneous groups of nucleosomes with different sizes, termed 'nucleosome clutches'. In addition to the regulation of chromatin structure, H1 is intimately involved in the control of multiple chromatin metabolism processes, such as DNA replication and repair, as well as modulation of the epigenetic landscape of the genome. The occupancy of H1 in chromosomes is not uniform. The dynamic, locus-specific, activity- and cell cycle-dependent distribution of H1 has essential implications for its biological activities. At the molecular level, H1 acts in a variety of distinct, biochemically separable mechanisms, including chromatin fibre compaction and limiting DNA accessibility to DNA-binding proteins, as well as tethering or specific inhibition of nuclear enzymes.