Single-nucleus multiomic analysis of Beckwith-Wiedemann syndrome liver reveals PPARA signaling enrichment and metabolic dysfunction.

Abstract

Beckwith-Wiedemann Syndrome (BWS) is an epigenetic overgrowth syndrome caused by methylation changes in the human 11p15 chromosomal locus. Patients with BWS may exhibit hepatomegaly, as well as an increased risk of hepatoblastoma. To understand the impact of these 11p15 changes in the liver, we performed a multiomic study [single nucleus RNA-sequencing (snRNA-seq) + single nucleus assay for transposable-accessible chromatin-sequencing (snATAC-seq)] of both BWS-liver and nonBWS-liver tumor-adjacent tissue. Our approach uncovers hepatocyte-specific enrichment of processes related to peroxisome proliferator-activated receptor alpha (PPARA). To confirm our findings, we differentiated a BWS induced pluripotent stem cell model into hepatocytes. Our data demonstrate the dysregulation of lipid metabolism in BWS-liver, which coincides with observed upregulation of PPARA during hepatocyte differentiation. BWS hepatocytes also exhibit decreased neutral lipids and increased fatty acid β-oxidation. We also observe increased reactive oxygen species byproducts in BWS hepatocytes, coinciding with increased oxidative DNA damage. This study proposes a putative mechanism for overgrowth and cancer predisposition in BWS liver due to perturbed metabolism.