Multi-omics on truncatingASXL1mutations in Bohring Opitz syndrome identify dysregulation of canonical and non-canonical Wnt signaling

Abstract

ABSTRACTASXL1(Additional sex combs-like 1) plays key roles in epigenetic regulation of early developmental gene expression.De novotruncating mutations inASXL1cause Bohring-Opitz syndrome (BOS, OMIM #605039), a rare neurodevelopmental condition characterized by severe intellectual disabilities, characteristic facial features, hypertrichosis, increased risk of Wilms tumor, and variable congenital anomalies including heart defects and severe skeletal defects giving rise to a typical ‘BOS posture’. These BOS-causingASXL1variants are also high-prevalence somatic driver mutations in acute myeloid leukemia (AML). We use primary cells from BOS individuals (n = 18) and controls (n = 49) to dissect gene regulatory changes caused byASXL1mutations using comprehensive multi-omics assays for chromatin accessibility (ATAC-seq), DNA methylation, histone methylation binding, and transcriptome in peripheral blood and skin fibroblasts. Our data shows that regardless of cell type,ASXL1mutations drive strong cross-tissue effects that disrupt multiple layers of the epigenome. The data showed a broad activation of canonical Wnt signaling at the transcriptional and protein levels and upregulation ofVANGL2, a planar cell polarity pathway protein that acts through non-canonical Wnt signaling to direct tissue patterning and cell migration. This multi-omics approach identifies the core impact ofASXL1mutations and therapeutic targets for BOS and myeloid leukemias.Brief summaryGermlineASXL1mutations that cause Bohring Optiz syndrome disrupt the epigenome and dysregulate gene expression resulting in activation of canonical and non-canonical Wnt signaling pathways.