Stage-specific histone modification profiles reveal global transitions in the Xenopus embryonic epigenome.

Vertebrate embryos are derived from a transitory pool of pluripotent cells. By the process of embryonic induction, these precursor cells are assigned to specific fates and differentiation programs. Histone post-translational modifications are thought to play a key role in the establishment and maintenance of stable gene expression patterns underlying these processes. While on gene level histone modifications are known to change during differentiation, very little is known about the quantitative fluctuations in bulk histone modifications during development. To investigate this issue we analysed histones isolated from four different developmental stages of Xenopus laevis by mass spectrometry. In toto, we quantified 59 modification states on core histones H3 and H4 from blastula to tadpole stages. During this developmental period, we observed in general an increase in the unmodified states, and a shift from histone modifications associated with transcriptional activity to transcriptionally repressive histone marks. We also compared these naturally occurring patterns with the histone modifications of murine ES cells, detecting large differences in the methylation patterns of histone H3 lysines 27 and 36 between pluripotent ES cells and pluripotent cells from Xenopus blastulae. By combining all detected modification transitions we could cluster their patterns according to their embryonic origin, defining specific histone modification profiles (HMPs) for each developmental stage. To our knowledge, this data set represents the first compendium of covalent histone modifications and their quantitative flux during normogenesis in a vertebrate model organism. The HMPs indicate a stepwise maturation of the embryonic epigenome, which may be causal to the progressing restriction of cellular potency during development

Complex exon-intron marking by histone modifications is not determined solely by nucleosome distribution

It has recently been shown that nucleosome distribution, histone modifications and RNA polymerase II (Pol II) occupancy show preferential association with exons (“exon-intron marking”), linking chromatin structure and function to co-transcriptional splicing in a variety of eukaryotes. Previous ChIP-sequencing studies suggested that these marking patterns reflect the nucleosomal landscape. By analyzing ChIP-chip datasets across the human genome in three cell types, we have found that this marking system is far more complex than previously observed. We show here that a range of histone modifications and Pol II are preferentially associated with exons. However, there is noticeable cell-type specificity in the degree of exon marking by histone modifications and, surprisingly, this is also reflected in some histone modifications patterns showing biases towards introns. Exon-intron marking is laid down in the absence of transcription on silent genes, with some marking biases changing or becoming reversed for genes expressed at different levels. Furthermore, the relationship of this marking system with splicing is not simple, with only some histone modifications reflecting exon usage/inclusion, while others mirror patterns of exon exclusion. By examining nucleosomal distributions in all three cell types, we demonstrate that these histone modification patterns cannot solely be accounted for by differences in nucleosome levels between exons and introns. In addition, because of inherent differences between ChIP-chip array and ChIP-sequencing approaches, these platforms report different nucleosome distribution patterns across the human genome. Our findings confound existing views and point to active cellular mechanisms which dynamically regulate histone modification levels and account for exon-intron marking. We believe that these histone modification patterns provide links between chromatin accessibility, Pol II movement and co-transcriptional splicing

HHMD: the human histone modification database

Histone modifications play important roles in chromatin remodeling, gene transcriptional regulation, stem cell maintenance and differentiation. Alterations in histone modifications may be linked to human diseases especially cancer. Histone modifications including methylation, acetylation and ubiquitylation probed by ChIP-seq, ChIP-chip and qChIP have become widely available. Mining and integration of histone modification data can be beneficial to novel biological discoveries. There has been no comprehensive data repository that is exclusive for human histone modifications. Therefore, we developed a relatively comprehensive database for human histone modifications. Human Histone Modification Database (HHMD, http://bioinfo.hrbmu.edu.cn/hhmd) focuses on the storage and integration of histone modification datasets that were obtained from laboratory experiments. The latest release of HHMD incorporates 43 location-specific histone modifications in human. To facilitate data extraction, flexible search options are built in HHMD. It can be searched by histone modification, gene ID, functional categories, chromosome location and cancer name. HHMD also includes a user-friendly visualization tool named HisModView, by which genome-wide histone modification map can be shown. HisModView facilitates the acquisition and visualization of histone modifications. The database also has manually curated information of histone modification dysregulation in nine human cancers

A Proposal on Quantum Histone Modification in Gene Expression

A quantum mechanical model on histone modification is proposed. Along with the methyl / acetate or other groups bound to the modified residues the torsion angles of the nearby histone chain are supposed to participate in the quantum transition cooperatively. The transition rate W is calculated based on the non-radiative quantum transition theory in adiabatic approximation. By using W's the reaction equations can be written for histone modification and the histone modification level can be calculable from the equations, which is decided by not only the atomic group bound to the modified residue, but also the nearby histone chain. The theory can explain the mechanism for the correlation between a pair of chromatin markers observed in histone modification. The temperature dependence and the coherence-length dependence of histone modification are deduced. Several points for checking the proposed theory and the quantum nature of histone modification are suggested as follows: 1, The relationship between lnW and 1/T is same as usual protein folding. The non-Arhenius temperature dependence of the histone modification level is predicted. 2, The variation of histone modification level through point mutation of some residues on the chain is predicted since the mutation may change the coherence-length of the system. 3, Multi-site modification obeys the quantum superposition law and the comparison between multi-site transition and single modification transition gives an additional clue to the testing of the quantum nature of histone modification.Comment: 10 page

High-resolution chromatin dynamics during a yeast stress response

Covalent histone modifications are highly conserved and play multiple roles in eukaryotic transcription regulation. Here, we mapped 26 histone modifications genome-wide in exponentially growing yeast and during a dramatic transcriptional reprogramming-the response to diamide stress. We extend prior studies showing that steady-state histone modification patterns reflect genomic processes, especially transcription, and display limited combinatorial complexity. Interestingly, during the stress response we document a modest increase in the combinatorial complexity of histone modification space, resulting from roughly 3% of all nucleosomes transiently populating rare histone modification states. Most of these rare histone states result from differences in the kinetics of histone modification that transiently uncouple highly correlated marks, with slow histone methylation changes often lagging behind the more rapid acetylation changes. Explicit analysis of modification dynamics uncovers ordered sequences of events in gene activation and repression. Together, our results provide a comprehensive view of chromatin dynamics during a massive transcriptional upheaval

Mechanistic stochastic model of histone modification pattern formation

BACKGROUND: The activity of a single gene is influenced by the composition of the chromatin in which it is embedded. Nucleosome turnover, conformational dynamics, and covalent histone modifications each induce changes in the structure of chromatin and its affinity for regulatory proteins. The dynamics of histone modifications and the persistence of modification patterns for long periods are still largely unknown. RESULTS: In this study, we present a stochastic mathematical model that describes the molecular mechanisms of histone modification pattern formation along a single gene, with non-phenomenological, physical parameters. We find that diffusion and recruitment properties of histone modifying enzymes together with chromatin connectivity allow for a rich repertoire of stochastic histone modification dynamics and pattern formation. We demonstrate that histone modification patterns at a single gene can be established or removed within a few minutes through diffusion and weak recruitment mechanisms of histone modification spreading. Moreover, we show that strong synergism between diffusion and weak recruitment mechanisms leads to nearly irreversible transitions in histone modification patterns providing stable patterns. In the absence of chromatin connectivity spontaneous and dynamic histone modification boundaries can be formed that are highly unstable, and spontaneous fluctuations cause them to diffuse randomly. Chromatin connectivity destabilizes this synergistic system and introduces bistability, illustrating state switching between opposing modification states of the model gene. The observed bistable long-range and localized pattern formation are critical effectors of gene expression regulation. CONCLUSION: This study illustrates how the cooperative interactions between regulatory proteins and the chromatin state generate complex stochastic dynamics of gene expression regulation

Computational study of associations between histone modification and protein-DNA binding in yeast genome by integrating diverse information

<p>Abstract</p> <p>Background</p> <p>In parallel with the quick development of high-throughput technologies, <it>in vivo (vitro) </it>experiments for genome-wide identification of protein-DNA interactions have been developed. Nevertheless, a few questions remain in the field, such as how to distinguish true protein-DNA binding (functional binding) from non-specific protein-DNA binding (non-functional binding). Previous researches tackled the problem by integrated analysis of multiple available sources. However, few systematic studies have been carried out to examine the possible relationships between histone modification and protein-DNA binding. Here this issue was investigated by using publicly available histone modification data in yeast.</p> <p>Results</p> <p>Two separate histone modification datasets were studied, at both the open reading frame (ORF) and the promoter region of binding targets for 37 yeast transcription factors. Both results revealed a distinct histone modification pattern between the functional protein-DNA binding sites and non-functional ones for almost half of all TFs tested. Such difference is much stronger at the ORF than at the promoter region. In addition, a protein-histone modification interaction pathway can only be inferred from the functional protein binding targets.</p> <p>Conclusions</p> <p>Overall, the results suggest that histone modification information can be used to distinguish the functional protein-DNA binding from the non-functional, and that the regulation of various proteins is controlled by the modification of different histone lysines such as the protein-specific histone modification levels.</p