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Extensive epigenetic and transcriptomic variability between genetically identical human B-lymphoblastoid cells with implications in pharmacogenomics research.

ABSTRACT: Genotyped human B-lymphoblastoid cell lines (LCLs) are widely used models in mapping quantitative trait loci for chromatin features, gene expression, and drug response. The extent of genotype-independent functional genomic variability of the LCL model, although largely overlooked, may inform association study design. In this study, we use flow cytometry, chromatin immunoprecipitation sequencing and mRNA sequencing to study surface marker patterns, quantify genome-wide chromatin changes (H3K27ac) and transcriptome variability, respectively, among five isogenic LCLs derived from the same individual. Most of the studied LCLs were non-monoclonal and had mature B cell phenotypes. Strikingly, nearly one-fourth of active gene regulatory regions showed significantly variable H3K27ac levels, especially enhancers, among which several were classified as clustered enhancers. Large, contiguous genomic regions showed signs of coordinated activity change. Regulatory differences were mirrored by mRNA expression changes, preferentially affecting hundreds of genes involved in specialized cellular processes including immune and drug response pathways. Differential expression of DPYD, an enzyme involved in 5-fluorouracil (5-FU) catabolism, was associated with variable LCL growth inhibition mediated by 5-FU. The extent of genotype-independent functional genomic variability might highlight the need to revisit study design strategies for LCLs in pharmacogenomics.

SUBMITTER: Ozgyin L

PROVIDER: S-EPMC6426863 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Extensive epigenetic and transcriptomic variability between genetically identical human B-lymphoblastoid cells with implications in pharmacogenomics research.

Ozgyin Lilla L Horvath Attila A Hevessy Zsuzsanna Z Balint Balint L BL

Scientific reports 20190320 1

Genotyped human B-lymphoblastoid cell lines (LCLs) are widely used models in mapping quantitative trait loci for chromatin features, gene expression, and drug response. The extent of genotype-independent functional genomic variability of the LCL model, although largely overlooked, may inform association study design. In this study, we use flow cytometry, chromatin immunoprecipitation sequencing and mRNA sequencing to study surface marker patterns, quantify genome-wide chromatin changes (H3K27ac) ...[more]

PMID: 30894562

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Project description:Human Papillomavirus (HPV) is an oncogenic virus that causes the highest number of viral-associated cancer cases and deaths worldwide, with more than 690,000 new cases per year and 342,000 deaths only for cervical cancer (CC). Although the incidence and mortality rates for CC are declining in countries where screening and vaccination programs have been implemented, other types of cancer in which HPV is involved, such as oropharyngeal cancer, are increasing, particularly in men. Mutational and transcriptional profiles of various HPV-associated neoplasms have been described, and accumulated evidence has shown the oncogenic capacity of E6, E7, and E5 genes of high-risk HPV. Interestingly, transcriptomic analysis has revealed that although a vast majority of the human genome is transcribed into RNAs, only 2% of transcripts are translated into proteins. The remaining transcripts lacking protein-coding potential are called non-coding RNAs. In addition to the transfer and ribosomal RNAs, there are regulatory non-coding RNAs classified according to size and structure in long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and small RNAs; such as microRNAs (miRNAs), piwi-associated RNAs (piRNAs), small nucleolar RNAs (snoRNAs) and endogenous short-interfering RNAs. Recent evidence has shown that lncRNAs, miRNAs, and circRNAs are aberrantly expressed under pathological conditions such as cancer. In addition, those transcripts are dysregulated in HPV-related neoplasms, and their expression correlates with tumor progression, metastasis, poor prognosis, and recurrence. Nuclear lncRNAs are epigenetic regulators involved in controlling gene expression at the transcriptional level through chromatin modification and remodeling. Moreover, disruption of the expression profiles of those lncRNAs affects multiple biological processes such as cell proliferation, apoptosis, and migration. This review highlights the epigenetic alterations induced by HPV, from infection to neoplastic transformation. We condense the epigenetic role of non-coding RNA alterations and their potential as biomarkers in transformation's early stages and clinical applications. We also summarize the molecular mechanisms of action of nuclear lncRNAs to understand better their role in the epigenetic control of gene expression and how they can drive the malignant phenotype of HPV-related neoplasia. Finally, we review several chemical and epigenetic therapy options to prevent and treat HPV-associated neoplasms.

Dataset Information

Extensive epigenetic and transcriptomic variability between genetically identical human B-lymphoblastoid cells with implications in pharmacogenomics research.

Publications

Extensive epigenetic and transcriptomic variability between genetically identical human B-lymphoblastoid cells with implications in pharmacogenomics research.

Similar Datasets

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