Solar Simulated Ultraviolet Radiation Induces Global Histone Hypoacetylation in Human Keratinocytes

Ultraviolet radiation (UVR) from sunlight is the primary effector of skin DNA damage. Chromatin remodeling and histone post-translational modification (PTM) are critical factors in repairing DNA damage and maintaining genomic integrity, however, the dynamic changes of histone marks in response to solar UVR are not well characterized. Here we report global changes in histone PTMs induced by solar simulated UVR (ssUVR). A decrease in lysine acetylation of histones H3 and H4, particularly at positions of H3 lysine 9, lysine 56, H4 lysine 5, and lysine 16, was found in human keratinocytes exposed to ssUVR. These acetylation changes were highly associated with ssUVR in a dose-dependent and time-specific manner. Interestingly, H4K16ac, a mark that is crucial for higher order chromatin structure, exhibited a persistent reduction by ssUVR that was transmitted through multiple cell divisions. In addition, the enzymatic activities of histone acetyltransferases were significantly reduced in irradiated cells, which may account for decreased global acetylation. Moreover, depletion of histone deacetylase SIRT1 in keratinocytes rescued ssUVR-induced H4K16 hypoacetylation. These results indicate that ssUVR affects both HDAC and HAT activities, leading to reduced histone acetylation.     

Discovering common combinatorial histone modification patterns in the human genome

Histone modifications play a crucial role in regulating gene expression and cell lineage determination and maintenance at the epigenetic level. To systematically investigate this phenomenon, this paper presented a statistical hybrid clustering algorithm to identify common combinatorial histone modification patterns. We applied the algorithm to 39 histone modification marks in human CD4 + T cells and detected 854 common combinatorial histone modification patterns. Our results could cover 211 (76.17%) patterns among 277 patterns identified by the tandem mass spectrometry experiments. Based on the frequency statistical analysis, it was found that the co-occurrence frequencies of 20 backbone modifications are greater than or close to 0.2 in the 854 patterns. we also found that 15 modifications (H2BK120ac, H4K91ac, H2BK20ac, etc.), three histone acetylations (H2AK9ac, H4K16ac, and H4K12ac) and five histone methylations (H3K79me1, H3K79me2, 3K79me3, H4K20me1, and H2BK5me1) were most likely prone to coexist respectively in these patterns. In addition, we found that DNA methylation tends to combine with histone acetylation rather than histone methylation.     

Histone acetylation and reactive oxygen species are involved in the preprophase arrest induced by sodium butyrate in maize roots

Histone acetylation plays a critical role in controlling chromatin structure, and reactive oxygen species (ROS) are involved in cell cycle progression. To study the relationship between histone acetylation and cell cycle progression in plants, sodium butyrate (NaB), a histone deacetylase (HDAC) inhibitor that can cause a significant increase in histone acetylation in both mammal and plant genomes, was applied to treat maize seedlings. The results showed that NaB had significant inhibition effects on different root zones at the tissue level and caused cell cycle arrest at preprophase in the root meristem zones. This effect was accompanied by a dramatic increase in the total level of acetylated lysine 9 on histone H3 (H3K9ac) and acetylated lysine 5 on histone H4 (H4K5ac). The exposure of maize roots in NaB led to a continuous rise of intracellular ROS concentration, accompanied by a higher electrolyte leakage ratio and malondialdehyde (MDA) relative value. The NaB-treated group displayed negative results in both TdT-mediated dUTP nick end labelling (TUNEL) and γ-H2AX immunostaining assays. The expression of topoisomerase genes was reduced after treatment with NaB. These results suggested that NaB increased the levels of H3K9ac and H4K5ac and could cause preprophase arrest accompanied with ROS formation leading to the inhibition of DNA topoisomerase.     

Identification of Epigenetic Biomarkers of Lung Adenocarcinoma through Multi-Omics Data Analysis

Epigenetic mechanisms such as DNA methylation or histone modifications are essential for the regulation of gene expression and development of tissues. Alteration of epigenetic modifications can be used as an epigenetic biomarker for diagnosis and as promising targets for epigenetic therapy. A recent study explored cancer-cell specific epigenetic biomarkers by examining different types of epigenetic modifications simultaneously. However, it was based on microarrays and reported biomarkers that were also present in normal cells at a low frequency. Here, we first analyzed multi-omics data (including ChIP-Seq data of six types of histone modifications: H3K27ac, H3K4me1, H3K9me3, H3K36me3, H3K27me3, and H3K4me3) obtained from 26 lung adenocarcinoma cell lines and a normal cell line. We identified six genes with both H3K27ac and H3K4me3 histone modifications in their promoter regions, which were not present in the normal cell line, but present in ≥85% (22 out of 26) and ≤96% (25 out of 26) of the lung adenocarcinoma cell lines. Of these genes, NUP210 (encoding a main component of the nuclear pore complex) was the only gene in which the two modifications were not detected in another normal cell line. RNA-Seq analysis revealed that NUP210 was aberrantly overexpressed among the 26 lung adenocarcinoma cell lines, although the frequency of NUP210 overexpression was lower (19.3%) in 57 lung adenocarcinoma tissue samples studied and stored in another database. This study provides a basis to discover epigenetic biomarkers highly specific to a certain cancer, based on multi-omics data at the cell population level.     

Alterations of lysine modifications on the histone H3 N-tail under drought stress conditions in Arabidopsis thaliana

Post-translational modification of histone N-tails affects eukaryotic gene activity. In Arabidopsis, the histone modification level correlates with gene activation and repression in vernalization and flowering processes, but there is little information on changes in histone modification status and nucleosome structure under abiotic stresses. We determined the temporal and spatial changes in nucleosome occupancy and levels of H3K4me3, H3K9ac, H3K14ac, H3K23ac and H3K27ac in the histone H3 N-tail on the regions of four Arabidopsis drought stress-inducible genes, RD29A, RD29B, RD20 and At2g20880 [corrected], under drought stress conditions by chromatin immunoprecipitation analysis. We found two types of regulatory mechanisms of nucleosome occupancy function in the drought stress response. For RD29A and RD29B genes, nucleosome occupancy of promoter regions is low compared with that of coding regions, and no notable nucleosome loss occurs under drought stress. In contrast, nucleosome density is gradually decreased in response to drought stress on RD20 and At2g20880 [corrected] genes. Enrichments of H3K4me3 and H3K9ac correlate with gene activation in response to drought stress in all four genes. Interestingly, establishment of H3K4me3 occurs after accumulation of RNAPII on the coding regions of RD29A and At2g20880 [corrected]. Enrichment of H3K23ac and H3K27ac occurs in response to drought stress on the coding regions of RD29B, RD20 and At2g20880 [corrected], but not on the coding region of At2g20880 [corrected]. Our results indicate that histone modifications on the H3 N-tail are altered with gene activation on the coding regions of drought stress-responsive genes under drought stress conditions and that several patterns of nucleosome changes function in the drought stress response.     

Arsenic Trioxide Reduces Global Histone H4 Acetylation at Lysine 16 through Direct Binding to Histone Acetyltransferase hMOF in Human Cells

Histone post-translational modification heritably regulates gene expression involved in most cellular biological processes. Experimental studies suggest that alteration of histone modifications affects gene expression by changing chromatin structure, causing various cellular responses to environmental influences. Arsenic (As), a naturally occurring element and environmental pollutant, is an established human carcinogen. Recently, increasing evidence suggests that As-mediated epigenetic mechanisms may be involved in its toxicity and carcinogenicity, but how this occurs is still unclear. Here we present evidence that suggests As-induced global histone H4K16 acetylation (H4K16ac) partly due to the direct physical interaction between As and histone acetyltransferase (HAT) hMOF (human male absent on first) protein, leading to the loss of hMOF HAT activity. Our data show that decreased global H4K16ac and increased deacetyltransferase HDAC4 expression occurred in arsenic trioxide (As₂O₃)-exposed HeLa or HEK293T cells. However, depletion of HDAC4 did not affect global H4K16ac, and it could not raise H4K16ac in cells exposed to As₂O₃, suggesting that HDAC4 might not directly be involved in histone H4K16 de-acetylation. Using As-immobilized agarose, we confirmed that As binds directly to hMOF, and that this interaction was competitively inhibited by free As₂O₃. Also, the direct interaction of As and C2CH zinc finger peptide was verified by MAIDI-TOF mass and UV absorption. In an in vitro HAT assay, As₂O₃ directly inhibited hMOF activity. hMOF over-expression not only increased resistance to As and caused less toxicity, but also effectively reversed reduced H4K16ac caused by As exposure. These data suggest a theoretical basis for elucidating the mechanism of As toxicity.     

Cell Cycle– and Chaperone-Mediated Regulation of H3K56ac Incorporation in Yeast

Acetylation of histone H3 lysine 56 is a covalent modification best known as a mark of newly replicated chromatin, but it has also been linked to replication-independent histone replacement. Here, we measured H3K56ac levels at single-nucleosome resolution in asynchronously growing yeast cultures, as well as in yeast proceeding synchronously through the cell cycle. We developed a quantitative model of H3K56ac kinetics, which shows that H3K56ac is largely explained by the genomic replication timing and the turnover rate of each nucleosome, suggesting that cell cycle profiles of H3K56ac should reveal most first-time nucleosome incorporation events. However, since the deacetylases Hst3/4 prevent use of H3K56ac as a marker for histone deposition during M phase, we also directly measured M phase histone replacement rates. We report a global decrease in turnover rates during M phase and a further specific decrease in turnover at several early origins of replication, which switch from rapidly replaced in G1 phase to stably bound during M phase. Finally, by measuring H3 replacement in yeast deleted for the H3K56 acetyltransferase Rtt109 and its two co-chaperones Asf1 and Vps75, we find evidence that Rtt109 and Asf1 preferentially enhance histone replacement at rapidly replaced nucleosomes, whereas Vps75 appears to inhibit histone turnover at those loci. These results provide a broad perspective on histone replacement/incorporation throughout the cell cycle and suggest that H3K56 acetylation provides a positive-feedback loop by which replacement of a nucleosome enhances subsequent replacement at the same location.     

组蛋白修饰对胚胎干细胞分化过程[]的调控机制

选用人类胚胎干细胞系和由人类胚胎干细胞系分化来的神经干细胞系为研究对象,分析组蛋白修饰对胚胎干细胞分化过程的调控作用。得到了两种细胞系差异表达基因转录起始位点侧翼区域内八种组蛋白修饰的分布模式,以及组蛋白修饰功能簇。研究表明在两类细胞系中,八种组蛋白修饰谱分布模式一致,且呈现两种分布类型; H3K27ac,H3K4me3和H3K9ac组成的功能簇是保守的;H3K27me3,H3K36me3和H3K79me1组成的功能簇以及H3K9me3和H3K27me3组成的功能簇在胚胎干细胞向神经干细胞分化的过程中消失。结果揭示了组蛋白修饰对胚胎干细胞系向神经干细胞系分化过程的部分调控机制,为该分化过程分子调控机制的研究提供部分重要的理论基础。