Deducing Causal Relationships among Different Histone Modifications, DNA Methylation and Gene Expression
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Histone modifications and DNA methylation are two major epigenetic factors regulating gene expression. However, the mechanism in which DNA methylation and histone modifications co-regulate gene expression was little studied. In our study, classifications of DNA methylation and gene expression showed the complicated relationship between gene expression and epigenetic factors. A Bayesian network was constructed by using the high-resolution maps of histone modifications, DNA methylation and gene expression in human CD4+ T cells to deduce causal and combinatorial relationships among them. PolII was found as the only direct regulator to gene expression, which was not found in prior studies. Our Bayesian network showed that epigenetic factors such as H3K4me3, H3K27me3 and DNA methylation are key regulators of gene expression, though indirectly. However they were considered to combinatorially stabilize the state and structure of chromatin.Keywords:
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Abstract The field of epigenetics is rapidly expanding, and has changed and revised traditional paradigms of inheritance. Epigenetics, literally “beyond genetics” or “in addition to genetics”, is defined as the study of heritable changes in gene expression that occur without a change in DNA sequence. Within this presentation, I will focus on modifications of histones, an important mechanism to convey epigenetic information. Histones, small proteins which serve as spools for DNA wrapped in nucleosomes, are critical regulators of the dynamic state of chromatin. They are subject to numerous posttranslational modifications, including acetylation, methylation, ubiquitylation, and phosphorylation. The best characterized modifications are acetylations and methylations. Increased acetylation of histones by histone acetyltransferases is associated with gene activation due to weakened charge attraction between DNA and histone; histone deacetylases in contrast remove acetyl groups leading to gene inactivation. Histone methylation mediated by histone methyltransferases has either positive effects or negative effects on gene expression depending on location and association of other protein complexes. In general, it is difficult to predict gene regulation based on the study of a single histone modification, since it is the combination of these modifications, also called the histone code, which ultimately controls gene expression. I will discuss details of the histone modification, how they regulate gene expression, and also their relevance in disease, especially breast cancer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr ES4-2.
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Epigenetics is the study of heritable and stable changes in gene expression that occur through alterations in the chromosome rather than in the DNA sequence. Despite not directly altering the DNA sequence, epigenetic mechanisms can regulate gene expression through chemical modifications of DNA bases and changes to the chromosomal superstructure in which DNA is packaged.Briefly, negatively charged DNA is packaged around a positively charged histone protein octamer, which contains 2 copies of histone proteins H2A, H2B, H3, and H4. This nucleoprotein complex is a nucleosome, the basic unit of chromatin. The nucleosomes of a continuous DNA polymer are connected by linker DNA and the complex is stabilized by histone protein H1. The aggregation of chromatin results in the formation of a chromosome. The chromatin of a chromosome exists as either loose, transcriptionally active euchromatin or dense, transcriptionally inactive heterochromatin. Chemical alterations to histone proteins can induce the formation of either the open euchromatin state, which facilitates gene expression by allowing transcription factors and enzymes to interact with the DNA, or the closed heterochromatin state, which suppresses gene expression by preventing initiation of transcription.In addition to histone changes, DNA methylation is an epigenetic mechanism associated with gene silencing when the methylation occurs in CpG islands of promoter sequences. Further, non-coding RNA sequences have shown to play a key role in the regulation of gene expression. These epigenetic modifications can be induced by several factors including age, diet, smoking, stress, and disease state. Epigenetic modifications are reversible, but they rarely remain through generations in humans despite persisting through multiple cycles of cell replication.
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Histone H3 lysine 4 trimethylation (H3K4me3) is a hallmark of transcription initiation, but how H3K4me3 is demethylated during gene repression is poorly understood. Jhd2, a JmjC domain protein, was recently identified as the major H3K4me3 histone demethylase (HDM) in Saccharomyces cerevisiae . Although JHD2 is required for removal of methylation upon gene repression, deletion of JHD2 does not result in increased levels of H3K4me3 in bulk histones, indicating that this HDM is unable to demethylate histones during steady-state conditions. In this study, we showed that this was due to the negative regulation of Jhd2 activity by histone H3 lysine 14 acetylation (H3K14ac), which colocalizes with H3K4me3 across the yeast genome. We demonstrated that loss of the histone H3-specific acetyltransferases (HATs) resulted in genome-wide depletion of H3K4me3, and this was not due to a transcription defect. Moreover, H3K4me3 levels were reestablished in HAT mutants following loss of JHD2 , which suggested that H3-specific HATs and Jhd2 serve opposing functions in regulating H3K4me3 levels. We revealed the molecular basis for this suppression by demonstrating that H3K14ac negatively regulated Jhd2 demethylase activity on an acetylated peptide in vitro. These results revealed the existence of a general mechanism for removal of H3K4me3 following gene repression.
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RNA-Directed DNA Methylation
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Abstract DNA methylation is the most important epigenetic element that activates the inhibition of gene transcription and is included in the pathogenesis of all types of malignancies. Remarkably, the effectors of DNA methylation are DNMTs (DNA methyltransferases) that catalyze de novo or keep methylation of hemimethylated DNA after the DNA replication process. DNA methylation structures in cancer are altered, with three procedures by which DNA methylation helps cancer development which are including direct mutagenesis, hypomethylation of the cancer genome, and also focal hypermethylation of the promoters of TSGs (tumor suppressor genes). Conspicuously, DNA methylation, nucleosome remodeling, RNA-mediated targeting, and histone modification balance modulate many biological activities that are essential and indispensable to the genesis of cancer and also can impact many epigenetic changes including DNA methylation and histone modifications as well as adjusting of non-coding miRNAs expression in prevention and treatment of many cancers. Epigenetics points to heritable modifications in gene expression that do not comprise alterations in the DNA sequence. The nucleosome is the basic unit of chromatin, consisting of 147 base pairs (bp) of DNA bound around a histone octamer comprised of one H3/H4 tetramer and two H2A/H2B dimers. DNA methylation is preferentially distributed over nucleosome regions and is less increased over flanking nucleosome-depleted DNA, implying a connection between nucleosome positioning and DNA methylation. In carcinogenesis, aberrations in the epigenome may also include in the progression of drug resistance. In this report, we report the rudimentary notes behind these epigenetic signaling pathways and emphasize the proofs recommending that their misregulation can conclude in cancer. These findings in conjunction with the promising preclinical and clinical consequences observed with epigenetic drugs against chromatin regulators, confirm the important role of epigenetics in cancer therapy.
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