In eukaryotic chromatin, islands of histone tail acetylation are found near transcription start sites and enhancers, whereas linker histones (LHs) are localized in intergenic regions with wild-type (WT) histone tails. However, the structural mechanisms by which acetylation, in combination with LH binding, modulates chromatin compaction and hence transcription regulation are unknown. To explore the folding propensity by which these features may govern gene expression, we analyze 20 kb fibers that contain regularly spaced acetylation islands of two sizes (2 or 5 kb) with various LH levels by mesoscale modeling. Specifically, we investigate the effect of acetylating each histone tail (H3, H4, H2A, and H2B) individually, in combination (H3 and H4, or all tails), and adding LH to WT regions. We find that fibers with acetylated H4 tails lose local contacts (<1 kb) and fibers with all tails acetylated have decreased long-range contacts in those regions. Tail interaction plots show that this opening of the fiber is driven by the loss of tail-tail interactions in favor of tail-parent core interactions and/or increase in free tails. When adding LH to WT regions, the fibers undergo hierarchical looping, enriching long-range contacts between WT and acetylated domains. For reference, adding LH to the entire fiber results in local condensation and loss of overall long-range contacts. These findings highlight the cooperation between histone tail acetylation and regulatory proteins like LH in directing folding and structural heterogeneity of chromatin fibers. The results advance our understanding of chromatin contact domains, which represent a pivotal part of the cell cycle, diseased states, and differentiation states in eukaryotic cells.
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