Chromatin Unfolding by Epigenetic Modifications Explained by Dramatic Impairment of Internucleosome Interactions: A...

Area of Science:

• Structural biology
• Epigenetics
• Computational biophysics

Background:

• Histone tails and epigenetic modifications are key to gene expression and chromatin structure.
• The precise structural mechanisms linking histone tails to chromatin states are not fully understood.
• Experimental characterization of chromatin structure is technically challenging.

Purpose of the Study:

• To elucidate the structural mechanisms by which histone tails and lysine acetylation influence chromatin folding and gene regulation.
• To investigate the conformational landscape of histone tails and their role in chromatin compaction.
• To understand the impact of epigenetic modifications on chromatin structure at a molecular level.

Main Methods:

• Multiscale computational modeling combining atomistic molecular dynamics simulations of dinucleosomes and histone tails with coarse-grained Monte Carlo simulations of nucleosome arrays.
• Simulations were performed in explicit solvent and ions using state-of-the-art force fields.
• Experimental validation using Nuclear Magnetic Resonance (NMR) measurements.

Main Results:

• Wild-type histone tails are flexible and disordered.
• Lysine acetylation significantly increases secondary-structure order in histone tails.
• Acetylation unfolds chromatin by reducing tail interactions crucial for fiber compaction.

Conclusions:

• Lysine acetylation of histone tails alters chromatin folding by promoting secondary structure and reducing internucleosome interactions.
• This provides a molecular explanation for how epigenetic modifications impact chromatin structure and gene regulation.
• The multiscale approach offers new insights into biomolecular complex dynamics.