Dynamic condensation of linker histone C-terminal domain regulates chromatin structure

The basic and intrinsically disordered C-terminal do-main (CTD) of the linker histone (LH) is essential for chromatin compaction. However, its conformation upon nucleosome binding and its impact on chro-matin organization remain unknown. Our mesoscale chromatin model with a flexible LH CTD captures a dynamic, salt-dependent condensation mechanism driven by charge neutralization between the LH and linker DNA. Namely, at low salt concentration, CTD condenses, but LH only interacts with the nucleo-some and one linker DNA, resulting in a semi-open nucleosome configuration; at higher salt, LH inter-acts with the nucleosome and two linker DNAs, pro-moting stem formation and chromatin compaction. CTD charge reduction unfolds the domain and de-condenses chromatin, a mechanism in consonance with reduced counterion screening in vitro and phos-phorylated LH in vivo. Divalent ions counteract this decondensation effect by maintaining nucleosome stems and expelling the CTDs to the fiber exterior. Additionally, we explain that the CTD folding depends on the chromatin fiber size, and we show that the asymmetric structure of the LH globular head is re-sponsible for the uneven interaction observed be-tween the LH and the linker DNAs. All these mecha-nisms may impact epigenetic regulation and higher levels of chromatin folding