Structural Role of RKS Motifs in Chromatin Interactions: A Molecular Dynamics Study of HP1 Bound to a Variably Modified Histone Tail

Papamokos, George; Tziatzos, George; Papageorgiou, Dimitrios G.; Georgatos, Spyros D.; Politou, Anastasia S.; Kaxiras, Efthimios

doi:10.1016/j.bpj.2012.03.030

Cited by 52 publications

(43 citation statements)

References 73 publications

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“…7). This undeniable identification by mass spectrometry was con- sistent with previous identifications of these modifications during mitosis (56), suggesting that H3S10 phosphorylation and H3K9 methylation could naturally occur simultaneously (57)(58)(59). Highly enriched H3 S10 phosphorylation and H3 K9 tri-methylation were revealed by flow cytometric analysis, demonstrating that monocytes without GMCSF stimulation are in G2/M phase as indicated by FC (Fig.…”

Section: Conclusion and Discussionsupporting

confidence: 84%

Quantitative Proteomics Reveals a Role for Epigenetic Reprogramming During Human Monocyte Differentiation

Nicholas

Tang²,

Zhang

et al. 2015

Molecular & Cellular Proteomics

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The differentiation of monocytes into macrophages and dendritic cells involves mechanisms for activation of the innate immune system in response to inflammatory stimuli, such as pathogen infection and environmental cues. Epigenetic reprogramming is thought to play an important role during monocyte differentiation. Complementary to cell surface markers, the characterization of monocytic cell lineages by mass spectrometry based protein/histone expression profiling opens a new avenue for studying immune cell differentiation. Here, we report the application of mass spectrometry and bioinformatics to identify changes in human monocytes during their differentiation into macrophages and dendritic cells. Our data show that linker histone H1 proteins are significantly down-regulated during monocyte differentiation. Although highly enriched H3K9-methyl/S10-phos/K14-acetyl tri-modification forms of histone H3 were identified in monocytes and macrophages, they were dramatically reduced in dendritic cells. In contrast, histone H4 K16 acetylation was found to be markedly higher in dendritic cells than in monocytes and macrophages. We also found that global hyperacetylation generated by the nonspecific histone deacetylase HDAC inhibitor Apicidin induces monocyte differentiation. Together, our data suggest that specific regulation of inter-and intra-histone modifications including H3 K9 methylation, H3 S10 phosphorylation, H3 K14 acetylation, and H4 K16 acetylation must occur in concert with chromatin remodeling by linker histones for cell cycle progression and differentiation of human myeloid cells into macrophages and dendritic cells. Molecular & Cellular

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Section: Conclusion and Discussionsupporting

confidence: 84%

Quantitative Proteomics Reveals a Role for Epigenetic Reprogramming During Human Monocyte Differentiation

Nicholas

Tang²,

Zhang

et al. 2015

Molecular & Cellular Proteomics

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“…We then selected the force field AMBER99SB*-ILDN to carry out the rest of the simulations. Force field parameters for acetylated lysines were taken from 29 for AMBER99SB*-ILDN and AMBER99SB (Papageorgiou’s parameters), and from 30 for CHARMM36 (Dejaegere’s parameters). To describe the nucleosomal DNA we used the AMBER99+parmBSC0 31 force field.…”

Section: Methodsmentioning

confidence: 99%

Chromatin Unfolding by Epigenetic Modifications Explained by Dramatic Impairment of Internucleosome Interactions: A Multiscale Computational Study

et al. 2015

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Histone tails and their epigenetic modifications play crucial roles in gene expression regulation by altering the architecture of chromatin. However, the structural mechanisms by which histone tails influence the interconversion between active and inactive chromatin remain unknown. Given the technical challenges in obtaining detailed experimental characterizations of the structure of chromatin, multiscale computations offer a promising alternative to model the effect of histone tails on chromatin folding. Here we combine multi-microsecond atomistic molecular dynamics simulations of dinucleosomes and histone tails in explicit solvent and ions, performed with three different state-of-the-art force fields and validated by experimental NMR measurements, with coarse-grained Monte Carlo simulations of 24-nucleosome arrays to describe the conformational landscape of histone tails, their roles in chromatin compaction, and the impact of lysine acetylation, a widespread epigenetic change, on both. 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. 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. Our approach also opens new avenues for multiscale processes of biomolecular complexes.

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“…Parameters for zinc were derived from the Zinc AMBER Force Field (ZAFF) developed by Merz group54. Force field parameters for acetyl lysine and NAD + are obtained from the literature5556. Partial charges for the AMC moiety and for resveratrol were fit with HF/6-31 G(d) calculations using Gaussian 09 package57 without geometry optimization.…”

Section: Methodsmentioning

confidence: 99%

Resveratrol serves as a protein-substrate interaction stabilizer in human SIRT1 activation

Hou

Rooklin

Fang

et al. 2016

Sci Rep

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Resveratrol is a natural compound found in red wine that has been suggested to exert its potential health benefit through the activation of SIRT1, a crucial member of the mammalian NAD+-dependent deacetylases. SIRT1 has emerged as an attractive therapeutic target for many aging related diseases, however, how its activity can only be activated toward some specific substrates by resveratrol has been poorly understood. Herein, by employing extensive molecular dynamics simulations as well as fragment-centric topographical mapping of binding interfaces, we have clarified current controversies in the literature and elucidated that resveratrol plays an important activation role by stabilizing SIRT1/peptide interactions in a substrate-specific manner. This new mechanism highlights the importance of the N-terminal domain in substrate recognition, explains the activity restoration role of resveratrol toward some “loose-binding” substrates of SIRT1, and has significant implications for the rational design of new substrate-specific SIRT1 modulators.

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Structural Role of RKS Motifs in Chromatin Interactions: A Molecular Dynamics Study of HP1 Bound to a Variably Modified Histone Tail

Cited by 52 publications

References 73 publications

Quantitative Proteomics Reveals a Role for Epigenetic Reprogramming During Human Monocyte Differentiation

Quantitative Proteomics Reveals a Role for Epigenetic Reprogramming During Human Monocyte Differentiation

Chromatin Unfolding by Epigenetic Modifications Explained by Dramatic Impairment of Internucleosome Interactions: A Multiscale Computational Study

Resveratrol serves as a protein-substrate interaction stabilizer in human SIRT1 activation

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