CEBPG Exhibits Allele-Specific Expression in Human Bronchial Epithelial Cells

Blomquist, Thomas M.; Crawford, Erin L.; Serna, Ivana de la; Williams, Kandace J.; Yoon, Youngsook; Hernandez, Dawn-Alita; Willey, James C.

doi:10.4137/grsb.s11879

Cited by 9 publications

(7 citation statements)

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“…48 CEBPG, by contrast, is mainly a lung cancer gene, with interindividual differences in expression level of CEBPG being associated with the risk of lung cancer. 49,50 In this study, CEBPG-Alu showed interindividual differences in methylation in the breast tissue (Fig. 4); assuming similar interindividual variation exists at the Alu locus in the lung, it may correlate with interindividual variation in CEBPG expression.…”

Section: Discussionsupporting

confidence: 55%

DNA methylation variation of human-specific Alu repeats

et al. 2016

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DNA methylation is the major repression mechanism for human retrotransposons, such as the Alu family. Here, we have determined the methylation levels associated with 5238 loci belonging to 2 Alu subfamilies, AluYa5 and AluYb8, using high-throughput targeted repeat element bisulfite sequencing (HT-TREBS). The results indicate that »90% of loci are repressed by high methylation levels. Of the remaining loci, many of the hypomethylated elements are found near gene promoters and show high levels of DNA methylation variation. We have characterized this variation in the context of tumorigenesis and interindividual differences. Comparison of a primary breast tumor and its matched normal tissue revealed early DNA methylation changes in »1% of AluYb8 elements in response to tumorigenesis. Simultaneously, AluYa5/ Yb8 elements proximal to promoters also showed differences in methylation of up to one order of magnitude, even between normal individuals. Overall, the current study demonstrates that early loss of methylation occurs during tumorigenesis in a subset of young Alu elements, suggesting their potential clinical relevance. However, approaches such as deep-bisulfite-sequencing of individual loci using HT-TREBS are required to distinguish clinically relevant loci from the background observed for AluYa5/Yb8 elements in general with regard to high levels of interindividual variation in DNA methylation.Abbreviations: BRCA1, Breast cancer 1, early onset; BRCA2, Breast cancer 2 early onset; CEBPG, CCAAT/enhancer binding protein (C/EBP)

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Section: Discussionsupporting

confidence: 55%

DNA methylation variation of human-specific Alu repeats

et al. 2016

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“…Heritable differences in gene expression between individuals are caused by DNA variants that affect the expression level of one allele ( cis -acting) or both alleles (trans-acting) of a gene [ 37 ]. Measurement of DAE is recognized as a powerful approach for identifying cis -acting regulatory variation [ 27 , 35 , 38 ]. We applied this technology to assess cis -rSNP activity and disease association at the exon level.…”

Section: Introductionmentioning

confidence: 99%

RNAseq analysis of bronchial epithelial cells to identify COPD-associated genes and SNPs

et al. 2018

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BackgroundThere is a need for more powerful methods to identify low-effect SNPs that contribute to hereditary COPD pathogenesis. We hypothesized that SNPs contributing to COPD risk through cis-regulatory effects are enriched in genes comprised by bronchial epithelial cell (BEC) expression patterns associated with COPD.MethodsTo test this hypothesis, normal BEC specimens were obtained by bronchoscopy from 60 subjects: 30 subjects with COPD defined by spirometry (FEV1/FVC < 0.7, FEV1% < 80%), and 30 non-COPD controls. Targeted next generation sequencing was used to measure total and allele-specific expression of 35 genes in genome maintenance (GM) genes pathways linked to COPD pathogenesis, including seven TP53 and CEBP transcription factor family members. Shrinkage linear discriminant analysis (SLDA) was used to identify COPD-classification models. COPD GWAS were queried for putative cis-regulatory SNPs in the targeted genes.ResultsOn a network basis, TP53 and CEBP transcription factor pathway gene pair network connections, including key DNA repair gene ERCC5, were significantly different in COPD subjects (e.g., Wilcoxon rank sum test for closeness, p-value = 5.0E-11). ERCC5 SNP rs4150275 association with chronic bronchitis was identified in a set of Lung Health Study (LHS) COPD GWAS SNPs restricted to those in putative regulatory regions within the targeted genes, and this association was validated in the COPDgene non-hispanic white (NHW) GWAS. ERCC5 SNP rs4150275 is linked (D’ = 1) to ERCC5 SNP rs17655 which displayed differential allelic expression (DAE) in BEC and is an expression quantitative trait locus (eQTL) in lung tissue (p = 3.2E-7). SNPs in linkage (D’ = 1) with rs17655 were predicted to alter miRNA binding (rs873601). A classifier model that comprised gene features CAT, CEBPG, GPX1, KEAP1, TP73, and XPA had pooled 10-fold cross-validation receiver operator characteristic area under the curve of 75.4% (95% CI: 66.3%–89.3%). The prevalence of DAE was higher than expected (p = 0.0023) in the classifier genes.ConclusionsGM genes comprised by COPD-associated BEC expression patterns were enriched for SNPs with cis-regulatory function, including a putative cis-rSNP in ERCC5 that was associated with COPD risk. These findings support additional total and allele-specific expression analysis of gene pathways with high prior likelihood for involvement in COPD pathogenesis.Electronic supplementary materialThe online version of this article (10.1186/s12890-018-0603-y) contains supplementary material, which is available to authorized users.

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“…In prior experimental studies we reported that germ-line variation is responsible for inter-individual variation in regulation of the key nucleotide excision repair gene ERCC5, one of the genes in the classifier reported here, and a key transcription regulator of GM genes, CEBPG [19–21]. Additional studies will be designed to identify DNA variants that contribute to regulation of other genes comprised by the classifier reported here.…”

Section: Discussionmentioning

confidence: 73%

A lung cancer risk classifier comprising genome maintenance genes measured in normal bronchial epithelial cells

et al. 2017

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BackgroundAnnual low dose CT (LDCT) screening of individuals at high demographic risk reduces lung cancer mortality by more than 20%. However, subjects selected for screening based on demographic criteria typically have less than a 10% lifetime risk for lung cancer. Thus, there is need for a biomarker that better stratifies subjects for LDCT screening. Toward this goal, we previously reported a lung cancer risk test (LCRT) biomarker comprising 14 genome-maintenance (GM) pathway genes measured in normal bronchial epithelial cells (NBEC) that accurately classified cancer (CA) from non-cancer (NC) subjects. The primary goal of the studies reported here was to optimize the LCRT biomarker for high specificity and ease of clinical implementation.MethodsTargeted competitive multiplex PCR amplicon libraries were prepared for next generation sequencing (NGS) analysis of transcript abundance at 68 sites among 33 GM target genes in NBEC specimens collected from a retrospective cohort of 120 subjects, including 61 CA cases and 59 NC controls. Genes were selected for analysis based on contribution to the previously reported LCRT biomarker and/or prior evidence for association with lung cancer risk. Linear discriminant analysis was used to identify the most accurate classifier suitable to stratify subjects for screening.ResultsAfter cross-validation, a model comprising expression values from 12 genes (CDKN1A, E2F1, ERCC1, ERCC4, ERCC5, GPX1, GSTP1, KEAP1, RB1, TP53, TP63, and XRCC1) and demographic factors age, gender, and pack-years smoking, had Receiver Operator Characteristic area under the curve (ROC AUC) of 0.975 (95% CI: 0.96–0.99). The overall classification accuracy was 93% (95% CI 88%–98%) with sensitivity 93.1%, specificity 92.9%, positive predictive value 93.1% and negative predictive value 93%. The ROC AUC for this classifier was significantly better (p < 0.0001) than the best model comprising demographic features alone.ConclusionsThe LCRT biomarker reported here displayed high accuracy and ease of implementation on a high throughput, quality-controlled targeted NGS platform. As such, it is optimized for clinical validation in specimens from the ongoing LCRT blinded prospective cohort study. Following validation, the biomarker is expected to have clinical utility by better stratifying subjects for annual lung cancer screening compared to current demographic criteria alone.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3287-4) contains supplementary material, which is available to authorized users.

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CEBPG Exhibits Allele-Specific Expression in Human Bronchial Epithelial Cells

Cited by 9 publications

References 37 publications

DNA methylation variation of human-specific Alu repeats

DNA methylation variation of human-specific Alu repeats

RNAseq analysis of bronchial epithelial cells to identify COPD-associated genes and SNPs

A lung cancer risk classifier comprising genome maintenance genes measured in normal bronchial epithelial cells

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