New Frontiers in Epigenetic Modifications

Garske, Adam L.; Denu, John M.

doi:10.1002/9783527627073.ch1

Cited by 2 publications

(2 citation statements)

References 89 publications

(136 reference statements)

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“…The above findings along with detailed analyses of residue-level interactions and energetics provide a plausible mechanism for H4 tail mediated chromatin compaction and K16 acetylation triggered unfolding of chromatin that could have important implications in chromatin biology, epigenetics, and drug discovery efforts. 35…”

Section: Introductionmentioning

confidence: 99%

Structure and binding of the H4 histone tail and the effects of lysine 16 acetylation

Yang

Arya

2011

Phys. Chem. Chem. Phys.

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The H4 histone tail plays a critical role in chromatin folding and regulation--it mediates strong interactions with the acidic patch of proximal nucleosomes and its acetylation at lysine 16 (K16) leads to partial unfolding of chromatin. The molecular mechanism associated with the H4 tail/acidic patch interactions and its modulation via K16 acetylation remains unknown. Here we employ a combination of molecular dynamics simulations, molecular docking calculations, and free energy computations to investigate the structure of the H4 tail in solution, the binding of the H4 tail with the acidic patch, and the effects of K16 acetylation. The H4 tail exhibits a disordered configuration except in the region Ala15-Lys20, where it exhibits a strong propensity for an α-helical structure. This α-helical region is found to dock very favorably into the acidic patch groove of a nucleosome with a binding free energy of approximately -7 kcal mol(-1). We have identified the specific interactions that stabilize this binding as well as the associated energetics. The acetylation of K16 is found to reduce the α-helix forming propensity of the H4 tail and K16's accessibility for mediating external interactions. More importantly, K16 acetylation destabilizes the binding of the H4 tail at the acidic patch by mitigating specific salt bridges and longer-ranged electrostatic interactions mediated by K16. Our study thus provides new microscopic insights into the compaction of chromatin and its regulation via posttranslational modifications of histone tails, which could be of interest to chromatin biology, cancer, epigenetics, and drug design.

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Section: Introductionmentioning

confidence: 99%

Structure and binding of the H4 histone tail and the effects of lysine 16 acetylation

Yang

Arya

2011

Phys. Chem. Chem. Phys.

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“…Epigenomics is the merged science of genomics and epigenetics (Raghavachari 2012 ). Functionally, epigenetics acts to regulate gene expression, gene silencing during genomic imprinting, apoptosis, X-chromosome inactivation, and tissue-specifi c gene activation (such as maintenance of stem cell pluripotency) (Garske and Denu 2009 ).…”

Section: Epigenetics and Epigenomicsmentioning

confidence: 99%

Genomics, Other “Omic” Technologies, Personalized Medicine, and Additional Biotechnology-Related Techniques

Sindelar

2013

Pharmaceutical Biotechnology

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New Frontiers in Epigenetic Modifications

Cited by 2 publications

References 89 publications

Structure and binding of the H4 histone tail and the effects of lysine 16 acetylation

Structure and binding of the H4 histone tail and the effects of lysine 16 acetylation

Genomics, Other “Omic” Technologies, Personalized Medicine, and Additional Biotechnology-Related Techniques

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