Awamleh, Z. | Search bioRxiv

bioRxiv2022

ASXL1 mutations that cause Bohring Opitz Syndrome (BOS) or acute myeloid leukemia share epigenomic and transcriptomic signatures

De novo, truncating variants of ASXL1 cause two distinct disorders: Bohring-Opitz Syndrome (BOS, OMIM #605039) a rare pediatric disorder characterized by multiorgan anomalies that disrupt normal brain, heart, and bone development causing severe intellectual disability or are somatic driver mutations causing acute myeloid leukemia(AML). Despite their distinct clinical presentations, we propose that ASXL1 mutations drive common epigenetic and transcriptomic dysregulation in BOS and AML. We analyzed DNA methylation (DNAm) and RNA-seq data from BOS patients (n=13) and controls (n=38) and publicly available DNAm of AML cases with (n=3) and without (n=3) ASXL1 mutations from The Cancer Genome Atlas (TCGA), and RNA-seq data from AML cases (n=27) from the Beat AML cohort. Using a DNA-methylation based episignature that we previously developed for BOS, we clustered AML, BOS and normal controls together. We showed that AML samples with ASXL1 mutations clustered closest to individuals with BOS, whereas individuals with AML without ASXL1 mutations clustered separately. We also observe common dysregulation of the transcriptome between BOS and AML with ASXL1 mutations compared to controls. Our transcriptomic analysis identified 821 significantly differentially expressed genes that were shared between both data sets and 74.9% showed differential expression in the same direction. BOS patients are rare and have some reports of tumors but no clear guidelines on cancer screening protocols. This represents the first direct comparison between distinct diseases that show common epigenetic and transcriptomic effects, and potentially common drug targets for patients harboring ASXL1 mutations on the epigenome and transcriptome. KEY POINTSO_LIAcute myeloid leukemias harboring somatic ASXL1 driver mutations and Bohring-Opitz syndrome caused by germline ASXL1 mutations share common epigenomic and transcriptomic dysregulation C_LIO_LIA gene-centric approach can inform molecular mechanisms across distinct disease types and point towards shared targetable pathways. C_LI

cancer biology↗

bioRxiv2022

Truncating ASXL1 mutations in Bohring-Opitz Syndrome dysregulate canonical and non-canonical Wnt Signaling

ASXL1 (Additional sex combs-like 1) plays key roles in epigenetic regulation of early developmental gene expression. De novo truncating mutations in ASXL1 cause 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-causing ASXL1 variants 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 by ASXL1 mutations 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, ASXL1 mutations 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 of VANGL2, 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 of ASXL1 mutations and therapeutic targets for BOS and myeloid leukemias. Brief summaryGermline ASXL1 mutations that cause Bohring Optiz syndrome disrupt the epigenome and dysregulate gene expression resulting in activation of canonical and non-canonical Wnt signaling pathways.

genetics↗