Single-nuclei transcriptional and chromatin accessibility profile of Beckwith-Wiedemann Syndrome liver suggests metabolic dysregulation driven by PPARA signaling

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 new 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. The integrated RNA+ATACseq multi-omic approach showed cell-type-specific enrichment and activation of the peroxisome proliferator-activated receptor ? (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, increased fatty acid beta oxidation, and increased lipid peroxidation, relative to controls. Excess reactive oxygen species (ROS) induces lipid peroxidation and cellular DNA damage. This study proposes a potential mechanism for overgrowth and cancer predisposition in BWS liver due to perturbed metabolism.