Abstract
The dynamic architecture of chromatin fibers, a key determinant of genome regulation, is poorly understood. Here, we employ multimodal single-molecule Förster resonance energy transfer studies to reveal structural states and their interconversion kinetics in chromatin fibers. We show that nucleosomes engage in short-lived (micro- to milliseconds) stacking interactions with one of their neighbors. This results in discrete tetranucleosome units with distinct interaction registers that interconvert within hundreds of milliseconds. Additionally, we find that dynamic chromatin architecture is modulated by the multivalent architectural protein heterochromatin protein 1α (HP1α), which engages methylated histone tails and thereby transiently stabilizes stacked nucleosomes. This compacted state nevertheless remains dynamic, exhibiting fluctuations on the timescale of HP1α residence times. Overall, this study reveals that exposure of internal DNA sites and nucleosome surfaces in chromatin fibers is governed by an intrinsic dynamic hierarchy from micro- to milliseconds, allowing the gene regulation machinery to access compact chromatin.
Highlights
The dynamic architecture of chromatin fibers, a key determinant of genome regulation, is poorly understood
Chromatin is critical to gene regulatory processes, as it dictates the accessibility of DNA to proteins such as transcription factors (TFs) and gene expression machinery[1]
Heterochromatin protein 1α (HP1α, CBX5), a defining component of transcriptionally silent heterochromatin, has been shown to interact with H3 tri-methylated at lysine 9 (H3K9me3)
Summary
The dynamic architecture of chromatin fibers, a key determinant of genome regulation, is poorly understood. We find that dynamic chromatin architecture is modulated by the multivalent architectural protein heterochromatin protein 1α (HP1α), which engages methylated histone tails and thereby transiently stabilizes stacked nucleosomes This compacted state remains dynamic, exhibiting fluctuations on the timescale of HP1α residence times. This study reveals that exposure of internal DNA sites and nucleosome surfaces in chromatin fibers is governed by an intrinsic dynamic hierarchy from micro- to milliseconds, allowing the gene regulation machinery to access compact chromatin. Using two fluorescent dye pairs with different distance sensitivities (i.e., Förster Radii, R0) allows us to measure a wide range of inter-dye distances (RDA) with sub-nm precision Employing this multipronged approach combined with dynamic structural biology methods (building on our FRET positioning and screening toolkit, FPS)[34], we identify distinct structural states in chromatin fibers and determine their exchange kinetics. Our study establishes a dynamic-register model of local chromatin fiber motions regulated by effector proteins
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