Beckwith-Wiedemann 综合征 (BWS) 是一种由人类 11p15 染色体位点甲基化变化引起的表观遗传过度生长综合征。 BWS 患者表现出组织过度生长，并且儿童肝脏和肾脏肿瘤的风险增加。为了了解这些 11p15 变化的影响，特别是在肝脏中，我们进行了单核 RNA 测序 (snRNA-seq) 和单核转座酶可及染色质测序分析 (snATAC-seq)，以生成配对的细胞类型-BWS肝脏和非BWS肝脏非肿瘤组织的特异性转录和染色质可及性特征。我们的整合 RNA ATACseq 多组学方法发现了肝细胞特异性富集和过氧化物酶体增殖物激活受体 α (PPARA)（一种肝脏代谢调节剂）的激活。为了证实我们的发现，我们利用了 BWS 诱导的多能干细胞 (iPSC) 模型，其中细胞分化为肝细胞。我们的数据表明 BWS 肝脏中脂质代谢失调，这与肝细胞分化过程中观察到的 PPARA 上调一致。与对照组相比，BWS 肝细胞表现出中性脂质减少和脂肪酸 β-氧化增加。我们还观察到 BWS 肝细胞中过氧化脂质形式的活性氧 (ROS) 副产物增加，这与氧化 DNA 损伤增加相一致。这项研究提出了由于代谢紊乱导致 BWS 肝脏过度生长和癌症易感性的假定机制。

Beckwith-Wiedemann Syndrome (BWS) is an epigenetic overgrowth syndrome caused by methylation changes in the human 11p15 chromosomal locus. Patients with BWS exhibit tissue overgrowth, as well as an increased risk of childhood neoplasms in the liver and kidney. To understand the impact of these 11p15 changes, specifically in the liver, we performed single-nucleus RNA sequencing (snRNA-seq) and single-nucleus assay for transposase-accessible chromatin with sequencing (snATAC-seq) to generate paired, cell-type-specific transcriptional and chromatin accessibility profiles of both BWS-liver and nonBWS-liver nontumorous tissue. Our integrated RNA+ATACseq multiomic approach uncovered hepatocyte-specific enrichment and activation of the peroxisome proliferator-activated receptor α (PPARA) - a liver metabolic regulator. To confirm our findings, we utilized a BWS-induced pluripotent stem cell (iPSC) model, where cells were differentiated into hepatocytes. Our data demonstrates the dysregulation of lipid metabolism in BWS-liver, which coincided with observed upregulation of PPARA during hepatocyte differentiation. BWS liver cells exhibited decreased neutral lipids and increased fatty acid β-oxidation, relative to controls. We also observed increased reactive oxygen species (ROS) byproducts in the form of peroxidated lipids in BWS hepatocytes, which coincided with increased oxidative DNA damage. This study proposes a putative mechanism for overgrowth and cancer predisposition in BWS liver due to perturbed metabolism.