Intragenic DNA methylation alters chromatin structure and elongation efficiency in mammalian cells

Lorincz, Matthew C.; Dickerson, David; Schmitt, Mike; Groudine, Mark

doi:10.1038/nsmb840

Cited by 429 publications

(402 citation statements)

References 50 publications

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“…In addition, inverse and positive correlations were observed between gene body methylation and expression. The cause and effect of DNA methylation within gene bodies is not fully understood; however, mechanisms leading to faulty gene expression have been postulated including the regulation of transcriptional elongation, 33 cell-type specific selection of alternative promoters, 34 modulating alternative RNA splicing, 35 or defining alternative polyadenylation sites. 36 Genes that are regulated by DNA methylation and provide a selective growth advantage to cancer cells have been referred to as epi-driver genes.…”

Section: Discussionmentioning

confidence: 99%

Integrated methylome and transcriptome analysis reveals novel regulatory elements in pediatric acute lymphoblastic leukemia

et al. 2015

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Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in children under the age of 15. In addition to genetic aberrations, epigenetic modifications such as DNA methylation are altered in cancer and impact gene expression. To identify epigenetic alterations in ALL, genome-wide methylation profiles were generated using the methylated CpG island recovery assay followed by next-generation sequencing. More than 25,000 differentially methylated regions (DMR) were observed in ALL patients with »90% present within intronic or intergenic regions. To determine the regulatory potential of the DMR, whole-transcriptome analysis was performed and integrated with methylation data. Aberrant promoter methylation was associated with the altered expression of genes involved in transcriptional regulation, apoptosis, and proliferation. Novel enhancer-like sequences were identified within intronic and intergenic DMR. Aberrant methylation in these regions was associated with the altered expression of neighboring genes involved in cell cycle processes, lymphocyte activation and apoptosis. These genes include potential epi-driver genes, such as SYNE1, PTPRS, PAWR, HDAC9, RGCC, MCOLN2, LYN, TRAF3, FLT1, and MELK, which may provide a selective advantage to leukemic cells. In addition, the differential expression of epigenetic modifier genes, pseudogenes, and non-coding RNAs was also observed accentuating the role of erroneous epigenetic gene regulation in ALL.

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Section: Discussionmentioning

confidence: 99%

Integrated methylome and transcriptome analysis reveals novel regulatory elements in pediatric acute lymphoblastic leukemia

et al. 2015

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“…However, it can be challenging to understand given the complex association of DNA methylation with gene expression. For examples, dense intragenic DNA methylation alters chromatin structure that reduces the efficiency of Polymerase II elongation, 30 the rate of transcriptional elongation regulating alternative splicing 31 ; transcription influenced by DNA methylation via chromatin remodeling 32 ; and methylation of gene bodies lead alternative splicing and disease-causing mutations. 33 In this study, 10% of the DM CpGs were significantly correlated with the gene expression.…”

Section: Discussionmentioning

confidence: 99%

Racial differences in genome-wide methylation profiling and gene expression in breast tissues from healthy women

et al. 2015

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Breast cancer is more common in European Americans (EAs) than in African Americans (AAs) but mortality from breast cancer is higher among AAs. While there are racial differences in DNA methylation and gene expression in breast tumors, little is known whether such racial differences exist in breast tissues of healthy women. Genome-wide DNA methylation and gene expression profiling was performed in histologically normal breast tissues of healthy women. Linear regression models were used to identify differentially-methylated CpG sites (CpGs) between EAs (n D 61) and AAs (n D 22). Correlations for methylation and expression were assessed. Biological functions of the differentially-methylated genes were assigned using the Ingenuity Pathway Analysis. Among 485 differentially-methylated CpGs by race, 203 were hypermethylated in EAs, and 282 were hypermethylated in AAs. Promoter-related differentially-methylated CpGs were more frequently hypermethylated in EAs (52%) than AAs (27%) while gene body and intergenic CpGs were more frequently hypermethylated in AAs. The differentially-methylated CpGs were enriched for cancer-associated genes with roles in cell death and survival, cellular development, and cell-to-cell signaling. In a separate analysis for correlation in EAs and AAs, different patterns of correlation were found between EAs and AAs. The correlated genes showed different biological networks between EAs and AAs; networks were connected by Ubiquitin C. To our knowledge, this is the first comprehensive genome-wide study to identify differences in methylation and gene expression between EAs and AAs in breast tissues from healthy women. These findings may provide further insights regarding the contribution of epigenetic differences to racial disparities in breast cancer.

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“…Very recently Lorincz et al [4] have shown that the efficiency of transcription can be seriously affected by methylation of non regulatory CpGs dispersed in the body of the gene.…”

Section: Cpg Dinucleotides Location and Func-tionmentioning

confidence: 99%

Dynamic and reversibility of heterochromatic gene silencing in human disease

et al. 2005

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In eukaryotic organisms cellular fate and tissue specific gene expression are regulated by the activity of proteins known as transcription factors that by interacting with specific DNA sequences direct the activation or repression of target genes. The post genomic era has shown that transcription factors are not the unique key regulators of gene expression. Epigenetic mechanisms such as DNA methylation, post-translational modifications of histone proteins, remodeling of nucleosomes and expression of small regulatory RNAs also contribute to regulation of gene expression, determination of cell and tissue specificity and assurance of inheritance of gene expression levels. The relevant contribution of epigenetic mechanisms to a proper cellular function is highlighted by the effects of their deregulation that cooperate with genetic alterations to the development of various diseases and to the establishment and progression of tumors.

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Intragenic DNA methylation alters chromatin structure and elongation efficiency in mammalian cells

Cited by 429 publications

References 50 publications

Integrated methylome and transcriptome analysis reveals novel regulatory elements in pediatric acute lymphoblastic leukemia

Integrated methylome and transcriptome analysis reveals novel regulatory elements in pediatric acute lymphoblastic leukemia

Racial differences in genome-wide methylation profiling and gene expression in breast tissues from healthy women

Dynamic and reversibility of heterochromatic gene silencing in human disease

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