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WIREs Syst Biol Med
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Regulatory variation: an emerging vantage point for cancer biology

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Transcriptional regulation involves complex and interdependent interactions of noncoding and coding regions of the genome with proteins that interact and modify them. Genetic variation/mutation in coding and noncoding regions of the genome can drive aberrant transcription and disease. In spite of accounting for nearly 98% of the genome comparatively little is known about the contribution of noncoding DNA elements to disease. Genome‐wide association studies of complex human diseases including cancer have revealed enrichment for variants in the noncoding genome. A striking finding of recent cancer genome re‐sequencing efforts has been the previously underappreciated frequency of mutations in epigenetic modifiers across a wide range of cancer types. Taken together these results point to the importance of dysregulation in transcriptional regulatory control in genesis of cancer. Powered by recent technological advancements in functional genomic profiling, exploration of normal and transformed regulatory networks will provide novel insight into the initiation and progression of cancer and open new windows to future prognostic and diagnostic tools. WIREs Syst Biol Med 2014, 6:37–59. doi: 10.1002/wsbm.1250 This article is categorized under: Biological Mechanisms > Regulatory Biology

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DNA methylation and transcriptional regulation. (a) DNA methylation and transcriptional regulation in normal cells. Dnmt3a and Dnmt3l form a tetramer to catalyze DNA methylation. MeCP2, member of MBD family, binds to methylated cytosine and recruits histone modifiers and chromatin remodelers to the site resulting in a more compact chromatin structure. These two mechanisms together keep the long terminal repeats (LTRs) silenced in the genome. Tet proteins catalyze 5mC (black circles) into 5hmC (gray circles) and lead to loss of methylation state in CGIs of promoters, thus activate transcription. TF binding at enhancer sites depletes Dnmts resulting in hypomethylation of the region. It may also recruit other activators that interact with the promoters and regulate transcription initiation. (b) DNA methylation and transcriptional regulation in cancer cells. Mutations in DNMT3A interrupt the tetramerization of Dnmt3a‐Dnmt3l and cause hypomethylation and aberrant activation of LTRs. Loss‐of‐function mutations or inhibition by oncometabolite 2HG of Tet will lead to loss of 5hmC and global hypermethylation, resulting in an altered methylation status and disrupted transcription initiation.
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Histone modifications and transcriptional regulation. (a) Regulation of gene expression by histone suppressive and permissive markers and associated regulatory factor in nontransformed cells. (b) Upregulation of suppressive markers and their associated factors or downregulation of permissive markers and their associated protein leads to aberrant expression of genes, such as tumor suppressor genes in transformed cells. (c) Upregulation of permissive histone marker and their associated regulatory factors or downregulation of suppressive histone markers and their associated regulatory factors leads to aberrant expression of genes in transformed cells. Variation in histone associated genes (red histone) can lead to abnormal expression of genes through disruption of regulatory factors.
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