期刊
EPIGENETICS
卷 16, 期 12, 页码 1295-1305出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15592294.2020.1861172
关键词
Beckwith-Wiedemann Syndrome; induced pluripotent stem cells; imprinting
资金
- Alex's Lemonade Stand Foundation for Childhood Cancer
- Damon Runyon Cancer Research Foundation
- National Cancer Institute [K08 CA193915]
- National Institute of General Medical Sciences [T32 GM07229, GM051279]
- St. Baldrick's Foundation
Genomic imprinting is a rare form of gene expression in mammals, with human imprinting disorders having diverse etiologies, the most common being BWS. The first iPSC model derived from patients with BWS demonstrates stable DNA methylation and gene expression patterns, providing a cell-based model for investigating the role of imprinting in the pathogenesis of BWS.
Genomic imprinting is a rare form of gene expression in mammals in which a small number of genes are expressed in a parent-of-origin-specific manner. The aetiology of human imprinting disorders is diverse and includes chromosomal abnormalities, mutations, and epigenetic dysregulation of imprinted genes. The most common human imprinting disorder is Beckwith-Wiedemann syndrome (BWS), frequently caused by uniparental isodisomy and DNA methylation alterations. Because these lesions cannot be easily engineered, induced pluripotent stem cells (iPSC) are a compelling alternative. Here, we describe the first iPSC model derived from patients with BWS. Due to the mosaic nature of BWS patients, both BWS and non-BWS iPSC lines were derived from the same patient's fibroblasts. Importantly, we determine that DNA methylation and gene expression patterns of the imprinted region in the iPSC lines reflect the parental cells and are stable over time. Additionally, we demonstrate that differential expression in insulin signalling, cell proliferation, and cell cycle pathways was seen in hepatocyte lineages derived from BWS lines compared to controls. Thus, this cell based-model can be used to investigate the role of imprinting in the pathogenesis of BWS in disease-relevant cell types.
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