Poster #81 - Snehal Nirgude

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

Snehal Nirgude, PhD1; Elisia D. Tichy, PhD1; Sanam L. Kavari1; Rose D. Pradieu1; Michael Xie1, PhD; Jennifer M. Kalish, MD PhD1,2 1Children's Hospital of Philadelphia, Philadelphia, USA. 2Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA

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 single nucleus multiomic study (snRNA-seq + snATAC-seq) of both BWS-liver and nonBWS-liver tumor-adjacent tissue. Our approach uncovered hepatocyte-specific enrichment of processes related to 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 coincided with observed upregulation of PPARA during hepatocyte differentiation. BWS hepatocytes exhibited decreased neutral lipids and increased fatty acid β-oxidation. We also observed 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.