A molecular dynamics study has detailed the structural mechanism by which histone tails influence the conversion between active and inactive forms of chromatin. [Darryl Leja, NHGRI]
A molecular dynamics study has detailed the structural mechanism by which histone tails influence the conversion between active and inactive forms of chromatin. [Darryl Leja, NHGRI]

Highly flexible, the histone tails that are attached to nucleosomes can be held high or tucked away, predisposing the nucleosomes to interact, or not. Held high, histone tails promote nucleosome interactions. Chromatin condenses, DNA stays inaccessible, and genes are turned off. Tucked away, histone tails impair nucleosome interactions. Chromatin loosens, DNA is exposed, and genes are turned on.

To detail histone’s role in activating or deactivating gene expression, researchers have run computer simulations of histone acetylation, one of the most common epigenetic modifications. These researchers, who are based at the Institute for Research in Biomedicine (IRB Barcelona), the University of Cambridge, and New York University, published their findings July 20 in the Journal of the American Chemical Society, in an article entitled, “Chromatin unfolding by epigenetic modifications explained by dramatic impairment of internucleosome interactions: a multiscale computational study.”

The article describes how the researchers, who were led by IRB Barcelona’s Modesto Orozco, Ph.D., combined multimicrosecond atomistic molecular dynamics simulations of dinucleosomes and histone tails in explicit solvent and ions. The researchers performed three different state-of-the-art force fields and validated their computational results with experimental NMR measurements. The also applied coarse-grained Monte Carlo simulations of 24-nucleosome arrays to describe the conformational landscape of histone tails and the impact of lysine acetylation.

“We find that while the wild-type tails are highly flexible and disordered, the dramatic increase of secondary-structure order by lysine acetylation unfolds chromatin by decreasing tail availability for crucial fiber-compacting internucleosome interactions,” wrote the study’s authors. “This molecular level description of the effect of histone tails and their charge modifications on chromatin folding explains the sequence sensitivity and underscores the delicate connection between local and global structural and functional effects.”

Essentially, the researchers found that histone tails with lysine acetylation acquire a certain structure. “By forming this structure, they become shorter and lose their ability to touch other nucleosomes,” said Dr. Orozco. “As a result, the internucleosomal contact that condenses unmodified chromatin, doesn't happen and this produces DNA molecules that are more accessible to effector proteins and therefore more active.”

The article's authors added that their computational approach could open new avenues for examining the multiscale processes of biomolecular complexes.

“This is the first mechanical explanation at the atomic level of an epigenetic effect, one of the most important, that connects an epigenetic modification with a phenotypic effect,” stated Dr. Orozco. “This leads us to believe that there is a similar explanation for other epigenetic modifications. There may be a very basic mechanism that accounts for the effect that they have on gene structure and expression.”

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