Derivation and investigation of the first human cell-based model of Beckwith-Wiedemann syndrome

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 etiology 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 signaling, 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.

基因组印记（Genomic imprinting）是哺乳动物中一类罕见的基因表达形式，仅少数基因会按照亲本来源特异性的方式完成表达。人类印记相关障碍的病因具有多样性，涵盖染色体异常、基因突变以及印记基因的表观遗传调控失常。最常见的人类印记障碍为贝威综合征（Beckwith-Wiedemann syndrome, BWS），其致病诱因通常为单亲二体（uniparental isodisomy）与DNA甲基化改变。由于此类病变难以通过工程化手段进行精准构建，诱导多能干细胞（induced pluripotent stem cells, iPSC）成为极具应用价值的替代研究模型。本研究首次报道了源自贝威综合征患者的诱导多能干细胞模型。鉴于贝威综合征患者存在嵌合性表型，研究团队从同一患者的成纤维细胞中分别构建了携带贝威综合征特征与不携带该特征的诱导多能干细胞系。重要的是，本研究证实，上述诱导多能干细胞系中印记区域的DNA甲基化与基因表达模式可忠实反映其亲本细胞的特征，且随时间推移保持稳定。此外，研究团队证实，与对照组相比，源自贝威综合征干细胞系的肝细胞谱系中，胰岛素信号通路、细胞增殖及细胞周期通路存在显著差异表达。因此，该细胞模型可用于在疾病相关的细胞类型中探究印记在贝威综合征发病机制中的具体作用。