Correlation among DNA Linker Length, Linker Histone Concentration, and Histone Tails in Chromatin

Abstract

Eukaryotic cells condense their genetic material in the nucleus in the form of chromatin, a macromolecular complex made of DNA and multiple proteins. The structure of chromatin is intimately connected to the regulation of all eukaryotic organisms, from amoebas to humans, but its organization remains largely unknown. The nucleosome repeat length (NRL) and the concentration of linker histones (ρLH) are two structural parameters that vary among cell types and cell cycles; the NRL is the number of DNA basepairs wound around each nucleosome core plus the number of basepairs linking successive nucleosomes. Recent studies have found a linear empirical relationship between the variation of these two properties for different cells, but its underlying mechanism remains elusive. Here we apply our established mesoscale chromatin model to explore the mechanisms responsible for this relationship, by investigating chromatin fibers as a function of NRL and ρLH combinations. We find that a threshold of linker histone concentration triggers the compaction of chromatin into well-formed 30-nm fibers; this critical value increases linearly with NRL, except for long NRLs, where the fibers remain disorganized. Remarkably, the interaction patterns between core histone tails and chromatin elements are highly sensitive to the NRL and ρLH combination, suggesting a molecular mechanism that could have a key role in regulating the structural state of the fibers in the cell. An estimate of the minimized work and volume associated with storage of chromatin fibers in the nucleus further suggests factors that could spontaneously regulate the NRL as a function of linker histone concentration. Both the tail interaction map and DNA packing considerations support the empirical NRL/ρLH relationship and offer a framework to interpret experiments for different chromatin conditions in the cell.

Elucidating the Influence of Linker Histone Variants on Chromatosome Dynamics and Energetics

“…43 The contrasting influence of linker histone isoforms on the chromatosome structure and energetics, and the extent to which they affect greater chromatin dynamics, remains unclear. [44][45][46] Using Brownian dynamic docking simulations, Öztürk et al found that GH5 displays a range of conformational flexibility and affects the overall chromatosome dynamics, including the linker DNA. 47 With similar techniques they later showed that even slightly varied linker histone sequences, including point mutations and posttranslational modifications, can significantly affect the chromatosome structure.…”

Dependence of the Linker Histone and Chromatin Condensation on the Nucleosome Environment

“…Furthermore, the LH type we follow (rat H1) is also longer by about 20 amino acids that the H1ºa system used by Fang et al 24 . Nevertheless, prior studies in agreement with a large array of experimental data 25, 26, 27, 29, 30, 28, 31, 32, 33, 34 suggest that in-silico studies help shed light on chromatin structure and energy trends, especially when conducted on a large set of system 25, 26, 27, 29, 30, 28, 31, 32, 33, 34 s with systematic parameters variations. Future models that allow DNA unwrapping, dynamic LH binding/unbinding, and other linker histone species can address these limitations.…”

“…For long linkers, the excess linker DNA forms other interactions with the tails and neighboring units, promoting bending and polymorphic states 32 . Previous work has also examined the LH-dependent fiber condensation 30, 31, 33 , and the synergistic folding of the LH and the chromatin fiber 25, 34 . LH condenses synergistically as the chromatin fiber forms a compact zigzag structure, and its LH condensation depends sensitively on the salt environment.…”

Kilobase Pair Chromatin Fiber Contacts Promoted by Living-System-Like DNA Linker Length Distributions and Nucleosome Depletion

“…This fits nicely with evidence that the cell may also actively regulate linker length in response to linker histone binding, which also varies across cell cycle stage. 67 …”