Transcription Factor Binding Profiles Reveal Cyclic Expression of Human Protein-coding Genes and Non-coding RNAs

Cheng, Chao; Ung, Matthew; Grant, Gavin D.; Whitfield, Michael L.

doi:10.1371/journal.pcbi.1003132

Cited by 7 publications

(7 citation statements)

References 49 publications

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“…As one of the most important cellular processes, the cell cycle is precisely regulated in all organisms. Dysregulation of the cell cycle can lead to catastrophic cellular events, e.g., premature apoptosis or abnormal proliferation, which are causes of cancers 39 . We found that the lncRNA and miRNA regulated key components of this pathway.…”

Section: Resultsmentioning

confidence: 99%

Genome-wide DNA methylome analysis reveals epigenetically dysregulated non-coding RNAs in human breast cancer

Zhang

et al. 2015

Sci Rep

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Despite growing appreciation of the importance of epigenetics in breast cancer, our understanding of epigenetic alterations of non-coding RNAs (ncRNAs) in breast cancer remains limited. Here, we explored the epigenetic patterns of ncRNAs in breast cancers using published sequencing-based methylome data, primarily focusing on the two most commonly studied ncRNA biotypes, long ncRNAs and miRNAs. We observed widely aberrant methylation in the promoters of ncRNAs, and this abnormal methylation was more frequent than that in protein-coding genes. Specifically, intergenic ncRNAs were observed to comprise a majority (51.45% of the lncRNAs and 51.57% of the miRNAs) of the aberrantly methylated ncRNA promoters. Moreover, we summarized five patterns of aberrant ncRNA promoter methylation in the context of genomic CpG islands (CGIs), in which aberrant methylation occurred not only on CGIs, but also in regions flanking CGI and in CGI-lacking promoters. Integration with transcriptional datasets enabled us to determine that the ncRNA promoter methylation events were associated with transcriptional changes. Furthermore, a panel of ncRNAs were identified as biomarkers that discriminated between disease phenotypes. Finally, the potential functions of aberrantly methylated ncRNAs were predicted, suggestiong that ncRNAs and coding genes cooperatively mediate pathway dysregulation during the development and progression of breast cancer.

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Section: Resultsmentioning

confidence: 99%

Genome-wide DNA methylome analysis reveals epigenetically dysregulated non-coding RNAs in human breast cancer

Zhang

et al. 2015

Sci Rep

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“…To confirm this gene set’s ability to infer E2F4’s regulatory activity level, we have used the gene set in conjunction with REACTIN to generate E2F4 iRASs in a cell cycle phase dataset [ 29 ], finding that E2F4 iRASs exhibits a periodic pattern and greatly outperforms E2F4 gene expression level in correlating with cell cycle phase (Figure 1 B). As E2F4 is a known critical regulator of the cell cycle [ 25 ], this result suggests that E2F4 iRASs reflect E2F4 functional activity and with much better accuracy than E2F4 gene expression level alone.…”

Section: Discussionmentioning

confidence: 99%

“…We focus on the E2F4 signature, because we have previously identified it as being prognostic in breast cancer in a large-scale computational screening analysis [ 24 ]. Further, in other work we have found E2F4’s activity level to be the most important of all TFs in predicting cell cycle phase in the HeLa and K562 cell lines, suggesting an essential role for E2F4 in cell cycle regulation [ 25 ]. Beyond our work, it is broadly considered that E2F4 plays an important role in both cell cycle arrest [ 26 ] and in modulating cell proliferation [ 27 ].…”

Section: Introductionmentioning

confidence: 97%

E2F4 regulatory program predicts patient survival prognosis in breast cancer

et al. 2014

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IntroductionGenetic and molecular signatures have been incorporated into cancer prognosis prediction and treatment decisions with good success over the past decade. Clinically, these signatures are usually used in early-stage cancers to evaluate whether they require adjuvant therapy following surgical resection. A molecular signature that is prognostic across more clinical contexts would be a useful addition to current signatures.MethodsWe defined a signature for the ubiquitous tissue factor, E2F4, based on its shared target genes in multiple tissues. These target genes were identified by chromatin immunoprecipitation sequencing (ChIP-seq) experiments using a probabilistic method. We then computationally calculated the regulatory activity score (RAS) of E2F4 in cancer tissues, and examined how E2F4 RAS correlates with patient survival.ResultsGenes in our E2F4 signature were 21-fold more likely to be correlated with breast cancer patient survival time compared to randomly selected genes. Using eight independent breast cancer datasets containing over 1,900 unique samples, we stratified patients into low and high E2F4 RAS groups. E2F4 activity stratification was highly predictive of patient outcome, and our results remained robust even when controlling for many factors including patient age, tumor size, grade, estrogen receptor (ER) status, lymph node (LN) status, whether the patient received adjuvant therapy, and the patient’s other prognostic indices such as Adjuvant! and the Nottingham Prognostic Index scores. Furthermore, the fractions of samples with positive E2F4 RAS vary in different intrinsic breast cancer subtypes, consistent with the different survival profiles of these subtypes.ConclusionsWe defined a prognostic signature, the E2F4 regulatory activity score, and showed it to be significantly predictive of patient outcome in breast cancer regardless of treatment status and the states of many other clinicopathological variables. It can be used in conjunction with other breast cancer classification methods such as Oncotype DX to improve clinical outcome prediction.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-014-0486-7) contains supplementary material, which is available to authorized users.

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“…Mis-regulation of the cell cycle can lead to catastrophic cellular events, e.g. premature apoptosis or abnormal proliferation of cells, which are the causes of cancers (Cheng et al 2013). We found that both the lncRNA and miRNA regulated the key components of this pathway.…”

Section: Cc-by-nc-nd 40 International License Peer-reviewed) Is the mentioning

confidence: 82%

Genome-wide DNA methylome analysis reveals novel epigenetically dysregulated non-coding RNAs in human breast cancer

Zhang

et al. 2014

Preprint

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The development of human breast cancer is driven by changes in the genetic and epigenetic landscape of the cell. Despite growing appreciation of the importance of epigenetics in breast cancers, our knowledge of epigenetic alterations of non-coding RNAs (ncRNAs) in breast cancers remains limited. Here, we explored the epigenetic patterns of ncRNAs in breast cancers via a sequencing-based comparative methylome analysis, mainly focusing on two most popular ncRNA biotypes, long non-coding RNAs (lncRNAs) and miRNAs. Besides global hypomethylation and extensive CpG islands (CGIs) hypermethylation, we observed widely aberrant methylation in the promoters of ncRNAs, which was higher than that of protein-coding genes. Specifically, intergenic ncRNAs were observed to contribute a large slice of the aberrantly methylated ncRNA promoters. Moreover, we summarized five patterns of ncRNA promoter aberrant methylation in the context of genomic CGIs, where aberrant methylation occurred not only on the CGIs, but also flanking regions and CGI sparse promoters. Integration with transcriptional datasets, we found that the ncRNA promoter methylation events were associated with transcriptional changes. Furthermore, a panel of ncRNAs were identified as biomarkers that were able to discriminate between disease phenotypes (AUCs>0.90). Finally, the potential functions for aberrantly methylated ncRNAs were predicted based on similar patterns, adjacency and/or target genes, highlighting that ncRNAs and coding genes coordinately mediated pathways dysregulation in the development and progression of breast cancers. This study presents the aberrant methylation patterns of ncRNAs, which will be a highly valuable resource for investigations at understanding epigenetic regulation of breast cancers.

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Transcription Factor Binding Profiles Reveal Cyclic Expression of Human Protein-coding Genes and Non-coding RNAs

Cited by 7 publications

References 49 publications

Genome-wide DNA methylome analysis reveals epigenetically dysregulated non-coding RNAs in human breast cancer

Genome-wide DNA methylome analysis reveals epigenetically dysregulated non-coding RNAs in human breast cancer

E2F4 regulatory program predicts patient survival prognosis in breast cancer

Genome-wide DNA methylome analysis reveals novel epigenetically dysregulated non-coding RNAs in human breast cancer

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