Chromatin fiber polymorphism triggered by variations of DNA linker lengths

Abstract

Deciphering the factors that control chromatin fiber structure is key to understanding fundamental chromosomal processes. Although details remain unknown, it is becoming clear that chromatin is polymorphic depending on internal and external factors. In particular, different lengths of the linker DNAs joining successive nucleosomes (measured in nucleosome-repeat lengths or NRLs) that characterize different cell types and cell cycle stages produce different structures. NRL is also nonuniform within single fibers, but how this diversity affects chromatin fiber structure is not clear. Here we perform Monte Carlo simulations of a coarse-grained oligonucleosome model to help interpret fiber structure subject to intrafiber NRL variations, as relevant to proliferating cells of interphase chromatin, fibers subject to remodeling factors, and regulatory DNA sequences. We find that intrafiber NRL variations have a profound impact on chromatin structure, with a wide range of different architectures emerging (highly bent narrow forms, canonical and irregular zigzag fibers, and polymorphic conformations), depending on the NRLs mixed. This stabilization of a wide range of fiber forms might allow NRL variations to regulate both fiber compaction and selective DNA exposure. The polymorphic forms spanning canonical to sharply bent structures, like hairpins and loops, arise from large NRL variations and are surprisingly more compact than uniform NRL structures. They are distinguished by tail-mediated far-nucleosome interactions, in addition to the near-nucleosome interactions of canonical 30-nm fibers. Polymorphism is consistent with chromatin's diverse biological functions and heterogeneous constituents. Intrafiber NRL variations, in particular, may contribute to fiber bending and looping and thus to distant communication in associated regulatory processes.coarse-grained modeling | chromatin polymorphism | nonuniform NRL | chromatin bending and looping T he DNA inside eukaryotic nuclei is not found free, but tightly packed along with histone and nonhistone proteins in the form of chromatin structures. Chromatin organization and structural transitions directly impact fundamental cellular processes such as DNA transcription, replication, repair, and recombination. However, our understanding of chromatin structure, how it is regulated by internal and external factors, and the relationship between structure and biological functions remain elusive. The challenge in solving these questions arises from the complex cellular milieu, chromatin's diverse and varying composition, and the limited resolution of experimental methods for large systems.Chromatin consists of a repeating sequence of nucleoprotein blocks (or nucleosomes) joined by DNA linker segments. The nucleosome structure is well understood at atomic resolution (1, 2). Its histone protein octamer (two copies each of H2A, H2B, H3, and H4) has ∼147 bp of DNA wrapped around it (1) and 10 highly positively charged and flexible tails (two N-terminal domains from each histone dimer and ...

Multiscale simulation of DNA

“…Early in vitro experiments [155] suggested the compaction of the nucleosome string into a 30 nm fiber, but the situation in vivois probably more complex ( Figure 1) and depends on many variables such as the linker length, ionic environment, the presence/absence of linker histones and the effect of chromatin remodelers [156,157].…”

“…We can divide computational approaches of chromatin structure into three basic [156,160], ionic environment [157,161], presence of linker histones [163] and different intra-and inter-chain physical interactions [156,157,[160][161][162][163][164]. In the top-down models the chromatin structure is derived by implementing experimental restraints coming from chromosome conformation capture techniques into a simple model of the chromatin fiber.…”

“…[176]. The Schlick model allows to study quite long (~50 nucleosomes) fibers [177] and has been used to study, for example, the influence of linker histone H1 [178], the DNA linker length [156], or the effect of certain epigenetic modifications on chromatin arrangement [117••]. Finally, worth to mention is the work by Müller et al Within the pure intermediate methods the objective is to move to much longer models than those accessible to the bottom-up approach, relying on the experimental data to correct the intrinsic limitations of the simple physical model used [159,165,168].…”

Untitled

“…(d) The model from Schlick and coworkers was used to study the chromatin fiber dynamics 50 . Apart from above-discussed application many other studies also performed using MD simulation and we recommend researcher to read specific articles to execute and understand deeper MD simulation analysis.…”

“…Chromatin fibers in the canonical and hairpin-like conformations are depicted (adapted with permission from 50 .…”