Barski, A. et al. Chromatin poises miRNA- and protein-coding genes for expression. Genome Res. 19, 1742-1751

Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Genome Research (Impact Factor: 14.63). 09/2009; 19(10):1742-51. DOI: 10.1101/gr.090951.109
Source: PubMed


Chromatin modifications have been implicated in the regulation of gene expression. While association of certain modifications with expressed or silent genes has been established, it remains unclear how changes in chromatin environment relate to changes in gene expression. In this article, we used ChIP-seq (chromatin immunoprecipitation with massively parallel sequencing) to analyze the genome-wide changes in chromatin modifications during activation of total human CD4(+) T cells by T-cell receptor (TCR) signaling. Surprisingly, we found that the chromatin modification patterns at many induced and silenced genes are relatively stable during the short-term activation of resting T cells. Active chromatin modifications were already in place for a majority of inducible protein-coding genes, even while the genes were silent in resting cells. Similarly, genes that were silenced upon T-cell activation retained positive chromatin modifications even after being silenced. To investigate if these observations are also valid for miRNA-coding genes, we systematically identified promoters for known miRNA genes using epigenetic marks and profiled their expression patterns using deep sequencing. We found that chromatin modifications can poise miRNA-coding genes as well. Our data suggest that miRNA- and protein-coding genes share similar mechanisms of regulation by chromatin modifications, which poise inducible genes for activation in response to environmental stimuli.

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    • "Core promoters of miRNA genes were promptly identified for depicting full-length primary transcripts [3] [4] [5]. Highthroughput sequencing datasets derived from epigenetic signature and TSS-relevant experiments unfold transcriptional start sites (TSSs) of miRNAs and offer a practical strategy to determine miRNA promoters [6] [7] [8] [9]. "
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    ABSTRACT: Noncoding, endogenous microRNAs (miRNAs) are fairly well known for regulating gene expression rather than protein coding. Dysregulation of miRNA gene, either upregulated or downregulated, may lead to severe diseases or oncogenesis, especially when the miRNA disorder involves significant bioreactions or pathways. Thus, how miRNA genes are transcriptionally regulated has been highlighted as well as target recognition in recent years. In this study, a large-scale investigation of novel cis- and trans-elements was undertaken to further determine TF-miRNA regulatory relations, which are necessary to unravel the transcriptional regulation of miRNA genes. Based on miRNA and annotated gene expression profiles, the term "coTFBS" was introduced to detect common transcription factors and the corresponding binding sites within the promoter regions of each miRNA and its coexpressed annotated genes. The computational pipeline was successfully established to filter redundancy due to short sequence motifs for TFBS pattern search. Eventually, we identified more convinced TF-miRNA regulatory relations for 225 human miRNAs. This valuable information is helpful in understanding miRNA functions and provides knowledge to evaluate the therapeutic potential in clinical research. Once most expression profiles of miRNAs in the latest database are completed, TF candidates of more miRNAs can be explored by this filtering approach in the future.
    Full-text · Article · Jun 2014 · BioMed Research International
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    • "There is also the potential role for epigenetic control microRNAs (miRNAs) on chromatin-modifying enzymes leading to effects in gene expression. Histone modifications and changes in chromatin structure can affect transcription and expression of miRNAs [69]; which are associated with the regulation of pathogenic pathways critical in insulin secretion, cholesterol synthesis and fat metabolism [70-72]. Increased telomeric activity and hTERT expression in HCC cases were also reported. "
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    ABSTRACT: Hepatocellular carcinoma is a multifactorial disease which is associated with a background of many causal risk factors. Diabetes mellitus however is one of the most common co-morbid illnesses found in hepatocellular carcinoma patients that are significantly associated with worsening of hepatocellular carcinoma development, patient prognosis and survival. Therefore, efforts have been focused on understanding the mechanisms underlying progression of hepatocellular carcinoma onset and development especially in diabetic patients. To our knowledge, there are no reports which address the impact of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) along with epigenetic regulations associated with increased risk of hepatocellular carcinoma confounded by diabetes mellitus. Therefore, this mini-review focuses on the possible intermediary mechanisms involved in worsening the onset and progression of hepatocellular carcinoma development confounded by diabetes mellitus. The first approach is to look at the role of inflammatory mediators (TNF-α and IL-6) in apoptosis and inflammation during hepatocarcinogenesis through monitoring levels of apoptotic regulators, B-cell lymphoma 2 protein which is encoded by BCL2 gene and apoptosis regulator BAX known as bcl-2-like protein 4 which is encoded by the BAX gene. The second approach is to focus on the possible epigenomic reprogramming that drives hepatocellular transformation since epigenetic modification of DNA is a key feature in the pathogenesis of hepatocarcinogenesis. Both approaches may suggest role of using Bcl2 and Bax as apoptotic and inflammatory markers for hepatocellular carcinoma detection as well as the importance impact of DNA methylation, hypomethylation or histone modifications as attractive candidates for early-detection biomarkers of hepatocellular carcinoma.
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    • "Genes responding rapidly to environmental stimuli, for example in immune response, have been shown in several studies to display only low levels of transcription, but with marks characteristic of an active chromatin state, also when the cell is unstimulated [38-41]. These genes were defined as being in a poised state, where the active chromatin poises the gene for rapid activation in response to external stimuli. "
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    ABSTRACT: Deciphering the most common modes by which chromatin regulates transcription, and how this is related to cellular status and processes is an important task for improving our understanding of human cellular biology. The FANTOM5 and ENCODE projects represent two independent large scale efforts to map regulatory and transcriptional features to the human genome. Here we investigate chromatin features around a comprehensive set of transcription start sites in four cell lines by integrating data from these two projects. Transcription start sites can be distinguished by chromatin states defined by specific combinations of both chromatin mark enrichment and the profile shapes of these chromatin marks. The observed patterns can be associated with cellular functions and processes, and they also show association with expression level, location relative to nearby genes, and CpG content. In particular we find a substantial number of repressed inter- and intra-genic transcription start sites enriched for active chromatin marks and Pol II, and these sites are strongly associated with immediate-early response processes and cell signaling. Associations between start sites with similar chromatin patterns are validated by significant correlations in their global expression profiles. The results confirm the link between chromatin state and cellular function for expressed transcripts, and also indicate that active chromatin states at repressed transcripts may poise transcripts for rapid activation during immune response.
    Full-text · Article · Mar 2014 · BMC Genomics
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