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Dissecting Epigenetic Silencing Complexity in the Mouse Lung Cancer Suppressor Gene Cadm1  [PDF]
Stella Marie Reamon-Buettner, Juergen Borlak
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0038531
Abstract: Disease-oriented functional analysis of epigenetic factors and their regulatory mechanisms in aberrant silencing is a prerequisite for better diagnostics and therapy. Yet, the precise mechanisms are still unclear and complex, involving the interplay of several effectors including nucleosome positioning, DNA methylation, histone variants and histone modifications. We investigated the epigenetic silencing complexity in the tumor suppressor gene Cadm1 in mouse lung cancer progenitor cell lines, exhibiting promoter hypermethylation associated with transcriptional repression, but mostly unresponsive to demethylating drug treatments. After predicting nucleosome positions and transcription factor binding sites along the Cadm1 promoter, we carried out single-molecule mapping with DNA methyltransferase M.SssI, which revealed in silent promoters high nucleosome occupancy and occlusion of transcription factor binding sites. Furthermore, M.SssI maps of promoters varied within and among the different lung cancer cell lines. Chromatin analysis with micrococcal nuclease also indicated variations in nucleosome positioning to have implications in the binding of transcription factors near nucleosome borders. Chromatin immunoprecipitation showed that histone variants (H2A.Z and H3.3), and opposing histone modification marks (H3K4me3 and H3K27me3) all colocalized in the same nucleosome positions that is reminiscent of epigenetic plasticity in embryonic stem cells. Altogether, epigenetic silencing complexity in the promoter region of Cadm1 is not only defined by DNA hypermethylation, but high nucleosome occupancy, altered nucleosome positioning, and ‘bivalent’ histone modifications, also likely contributed in the transcriptional repression of this gene in the lung cancer cells. Our results will help define therapeutic intervention strategies using epigenetic drugs in lung cancer.
UHRF1 Links the Histone Code and DNA Methylation to Ensure Faithful Epigenetic Memory Inheritance
Christian Bronner, Guy Fuhrmann, Frédéric L Chédin, Marcella Macaluso and Sirano Dhe-Paganon
Genetics & Epigenetics , 2012,
Abstract: Epigenetics is the study of the transmission of cell memory through mitosis or meiosis that is not based on the DNA sequence. At the molecular level the epigenetic memory of a cell is embedded in DNA methylation, histone post-translational modifications, RNA interference and histone isoform variation. There is a tight link between histone post-translational modifications (the histone code) and DNA methylation, as modifications of histones contribute to the establishment of DNA methylation patterns and vice versa. Interestingly, proteins have recently been identified that can simultaneously read both methylated DNA and the histone code. UHRF1 fulfills these requirements by having unique structural domains that allow concurrent recognition of histone modifications and methylated DNA. Herein, we review our current knowledge of UHRF1 and discuss how this protein ensures the link between histone marks and DNA methylation. Understanding the molecular functions of this protein may reveal the physiological relevance of the linkage between these layers of epigenetic marks.
Understanding the Connection between Epigenetic DNA Methylation and Nucleosome Positioning from Computer Simulations  [PDF]
Guillem Portella ,Federica Battistini ,Modesto Orozco
PLOS Computational Biology , 2013, DOI: 10.1371/journal.pcbi.1003354
Abstract: Cytosine methylation is one of the most important epigenetic marks that regulate the process of gene expression. Here, we have examined the effect of epigenetic DNA methylation on nucleosomal stability using molecular dynamics simulations and elastic deformation models. We found that methylation of CpG steps destabilizes nucleosomes, especially when these are placed in sites where the DNA minor groove faces the histone core. The larger stiffness of methylated CpG steps is a crucial factor behind the decrease in nucleosome stability. Methylation changes the positioning and phasing of the nucleosomal DNA, altering the accessibility of DNA to regulatory proteins, and accordingly gene functionality. Our theoretical calculations highlight a simple physical-based explanation on the foundations of epigenetic signaling.
Epigenetic Activation of SOX11 in Lymphoid Neoplasms by Histone Modifications  [PDF]
Maria Carmela Vegliante, Cristina Royo, Jara Palomero, Itziar Salaverria, Balazs Balint, Idoia Martín-Guerrero, Xabier Agirre, Amaia Lujambio, Julia Richter, Silvia Xargay-Torrent, Silvia Bea, Luis Hernandez, Anna Enjuanes, María José Calasanz, Andreas Rosenwald, German Ott, José Roman-Gomez, Felipe Prosper, Manel Esteller, Pedro Jares, Reiner Siebert, Elias Campo, José I. Martín-Subero, Virginia Amador
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0021382
Abstract: Recent studies have shown aberrant expression of SOX11 in various types of aggressive B-cell neoplasms. To elucidate the molecular mechanisms leading to such deregulation, we performed a comprehensive SOX11 gene expression and epigenetic study in stem cells, normal hematopoietic cells and different lymphoid neoplasms. We observed that SOX11 expression is associated with unmethylated DNA and presence of activating histone marks (H3K9/14Ac and H3K4me3) in embryonic stem cells and some aggressive B-cell neoplasms. In contrast, adult stem cells, normal hematopoietic cells and other lymphoid neoplasms do not express SOX11. Such repression was associated with silencing histone marks H3K9me2 and H3K27me3. The SOX11 promoter of non-malignant cells was consistently unmethylated whereas lymphoid neoplasms with silenced SOX11 tended to acquire DNA hypermethylation. SOX11 silencing in cell lines was reversed by the histone deacetylase inhibitor SAHA but not by the DNA methyltransferase inhibitor AZA. These data indicate that, although DNA hypermethylation of SOX11 is frequent in lymphoid neoplasms, it seems to be functionally inert, as SOX11 is already silenced in the hematopoietic system. In contrast, the pathogenic role of SOX11 is associated with its de novo expression in some aggressive lymphoid malignancies, which is mediated by a shift from inactivating to activating histone modifications.
Dynamic Epigenetic Regulation of Gene Expression during the Life Cycle of Malaria Parasite Plasmodium falciparum  [PDF]
Archna P. Gupta,Wai Hoe Chin,Lei Zhu,Sachel Mok,Yen-Hoon Luah,Eng-How Lim,Zbynek Bozdech
PLOS Pathogens , 2013, DOI: 10.1371/journal.ppat.1003170
Abstract: Epigenetic mechanisms are emerging as one of the major factors of the dynamics of gene expression in the human malaria parasite, Plasmodium falciparum. To elucidate the role of chromatin remodeling in transcriptional regulation associated with the progression of the P. falciparum intraerythrocytic development cycle (IDC), we mapped the temporal pattern of chromosomal association with histone H3 and H4 modifications using ChIP-on-chip. Here, we have generated a broad integrative epigenomic map of twelve histone modifications during the P. falciparum IDC including H4K5ac, H4K8ac, H4K12ac, H4K16ac, H3K9ac, H3K14ac, H3K56ac, H4K20me1, H4K20me3, H3K4me3, H3K79me3 and H4R3me2. While some modifications were found to be associated with the vast majority of the genome and their occupancy was constant, others showed more specific and highly dynamic distribution. Importantly, eight modifications displaying tight correlations with transcript levels showed differential affinity to distinct genomic regions with H4K8ac occupying predominantly promoter regions while others occurred at the 5′ ends of coding sequences. The promoter occupancy of H4K8ac remained unchanged when ectopically inserted at a different locus, indicating the presence of specific DNA elements that recruit histone modifying enzymes regardless of their broad chromatin environment. In addition, we showed the presence of multivalent domains on the genome carrying more than one histone mark, highlighting the importance of combinatorial effects on transcription. Overall, our work portrays a substantial association between chromosomal locations of various epigenetic markers, transcriptional activity and global stage-specific transitions in the epigenome.
Epigenetic regulation: methylation of histone and non-histone proteins
Fei Lan,Yang Shi
Science China Life Sciences , 2009, DOI: 10.1007/s11427-009-0054-z
Abstract: Histone methylation is believed to play important roles in epigenetic memory in various biological processes. However, questions like whether the methylation marks themselves are faithfully transmitted into daughter cells and through what mechanisms are currently under active investigation. Previously, methylation was considered to be irreversible, but the recent discovery of histone lysine demethylases revealed a dynamic nature of histone methylation regulation on four of the main sites of methylation on histone H3 and H4 tails (H3K4, H3K9, H3K27 and H3K36). Even so, it is still unclear whether demethylases specific for the remaining two sites, H3K79 and H4K20, exist. Furthermore, besides histone proteins, the lysine methylation and demethylation also occur on non-histone proteins, which are probably subjected to similar regulation as histones. This review discusses recent progresses in protein lysine methylation regulation focusing on the above topics, while referring readers to a number of recent reviews for the biochemistry and biology of these enzymes
Epigenetic regulation: methylation of histone and non-histone proteins

Fei Lan,Yang Shi,

中国科学C辑(英文版) , 2009,
Abstract: Histone methylation is believed to play important roles in epigenetic memory in various biological processes. However, questions like whether the methylation marks themselves are faithfully transmitted into daughter cells and through what mechanisms are currently under active investigation. Previously, methylation was considered to be irreversible, but the recent discovery of histone lysine demethylases revealed a dynamic nature of histone methylation regulation on four of the main sites of methylation on histone H3 and H4 tails (H3K4, H3K9, H3K27 and H3K36). Even so, it is still unclear whether demethylases specific for the remaining two sites, H3K79 and H4K20, exist. Furthermore, besides histone proteins, the lysine methylation and demethylation also occur on non-histone proteins, which are probably subjected to similar regulation as histones. This review discusses recent progresses in protein lysine methylation regulation focusing on the above topics, while referring readers to a number of recent reviews for the biochemistry and biology of these enzymes
Epigenetic changes in colorectal cancer  [cached]
Yan Jia,Mingzhou Guo
Chinese Journal of Cancer , 2013, DOI: 10.5732/cjc.011.10245
Abstract: Epigenetic changes frequently occur in human colorectal cancer. Genomic global hypomethylation, gene promoter region hypermethylation, histone modifications, and alteration of miRNA patterns are major epigenetic changes in colorectal cancer. Loss of imprinting(LOI) is associated with colorectal neoplasia. Folate deficiency may cause colorectal carcinogenesis by inducing gene-specific hypermethylation and genomic global hypomethylation. HDAC inhibitors and demethylating agents have been approved by the FDA for myelodysplastic syndrome and leukemia treatment. Non-coding RNA is regarded as another kind of epigenetic marker in colorectal cancer. This review is mainly focused on DNA methylation, histone modification, and microRNA changes in colorectal cancer.
Global profiling of histone and DNA methylation reveals epigenetic-based regulation of gene expression during epithelial to mesenchymal transition in prostate cells
Xi-Song Ke, Yi Qu, Yang Cheng, Wen-Cheng Li, Varda Rotter, Anne ?yan, Karl-Henning Kalland
BMC Genomics , 2010, DOI: 10.1186/1471-2164-11-669
Abstract: Genome-wide profiling of histone methylations (H3K4me3 and H3K27me3) and DNA methylation (DNAMe) was applied to three cell lines at different stages of a stepwise prostate cell model involving EMT and subsequent accumulation of malignant features. Integrated analyses of epigenetic promoter modifications and gene expression changes revealed strong correlations between the dynamic changes of histone methylations and gene expression. DNA methylation was weaker associated with global gene repression, but strongly correlated to gene silencing when genes co-modified by H3K4me3 were excluded. For genes labeled with multiple epigenetic marks in their promoters, the level of transcription was associated with the net signal intensity of the activating mark H3K4me3 minus the repressive marks H3K27me3 or DNAMe, indicating that the effect on gene expression of bivalent marks (H3K4/K27me3 or H3K4me3/DNAMe) depends on relative modification intensities. Sets of genes, including epithelial cell junction and EMT associated fibroblast growth factor receptor genes, showed corresponding changes concerning epigenetic modifications and gene expression during EMT.This work presents the first blueprint of epigenetic modifications in an epithelial cell line and the progeny that underwent EMT and shows that specific histone methylations are extensively involved in gene expression reprogramming during EMT and subsequent accumulation of malignant features. The observation that transcription activity of bivalently marked genes depends on the relative labeling intensity of individual marks provides a new view of quantitative regulation of epigenetic modification.Carcinomas arise from normal epithelial tissues in a multistep process. The breakdown of epithelial cell homeostasis leading to aggressive cancer progression corresponds with the loss of epithelial characteristics and the acquisition of migratory phenotypes, referred to as epithelial to mesenchymal transition (EMT), and is believed to be
Statistical Mechanics Model for the Dynamics of Collective Epigenetic Histone Modification  [PDF]
Hang Zhang,Xiao-Jun Tian,Abhishek Mukhopadhyay,K. S. Kim,Jianhua Xing
Quantitative Biology , 2014, DOI: 10.1103/PhysRevLett.112.068101
Abstract: Epigenetic histone modifications play an important role in the maintenance of different cell phenotypes. The exact molecular mechanism for inheritance of the modification patterns over cell generations remains elusive. We construct a Potts-type model based on experimentally observed nearest-neighbor enzyme lateral interactions and nucleosome covalent modification state biased enzyme recruitment. The model can lead to effective nonlocal interactions among nucleosomes suggested in previous theoretical studies, and epigenetic memory is robustly inheritable against stochastic cellular processes.
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