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Multiomics of Bohring-Opitz syndrome truncating ASXL1 mutations identify canonical and noncanonical Wnt signaling dysregulation
Isabella Lin, … , Rosanna Weksberg, Valerie A. Arboleda
Isabella Lin, … , Rosanna Weksberg, Valerie A. Arboleda
Published April 13, 2023
Citation Information: JCI Insight. 2023;8(10):e167744. https://doi.org/10.1172/jci.insight.167744.
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Research Article Development Genetics

Multiomics of Bohring-Opitz syndrome truncating ASXL1 mutations identify canonical and noncanonical Wnt signaling dysregulation

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Abstract

ASXL1 (additional sex combs–like 1) plays key roles in epigenetic regulation of early developmental gene expression. De novo protein-truncating mutations in ASXL1 cause Bohring-Opitz syndrome (BOS; OMIM #605039), a rare neurodevelopmental condition characterized by severe intellectual disabilities, distinctive 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. We used primary cells from individuals with BOS (n = 18) and controls (n = 49) to dissect gene regulatory changes caused by ASXL1 mutations using comprehensive multiomics assays for chromatin accessibility (ATAC-seq), DNA methylation, histone methylation binding, and transcriptome in peripheral blood and skin fibroblasts. Our data show 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, which encodes a planar cell polarity pathway protein that acts through noncanonical Wnt signaling to direct tissue patterning and cell migration. This multiomics approach identifies the core impact of ASXL1 mutations and therapeutic targets for BOS and myeloid leukemias.

Authors

Isabella Lin, Angela Wei, Zain Awamleh, Meghna Singh, Aileen Ning, Analeyla Herrera, REACH Biobank and Registry, Bianca E. Russell, Rosanna Weksberg, Valerie A. Arboleda

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Figure 1

Multiomics study design for Bohring-Opitz syndrome (BOS) caused by pathogenic mutations in ASXL1.

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Multiomics study design for Bohring-Opitz syndrome (BOS) caused by patho...
(A) Schematic representation of the ASXL1 transcript (ENST00000375687.10) and protein (GenBank: NM_015338.6; GRCh37), its functional domains, and mutations causing BOS. Mutations listed correspond to patients in this study and are tagged with a Pt identifier. (B) Peripheral blood and dermal fibroblasts were collected and underwent epigenomic assays for ATAC-seq, CUT&RUN, and DNA methylation, and global transcriptome analysis using RNA-seq. (C) Across the multiomics assays and 2 specimen types, we had 8 of 18 BOS samples with fibroblast assays and 14 of 18 with blood assays. Four of 18 BOS patients had data from assays across both specimen types. (D) Promoter hypermethylation and closed chromatin, which can be examined with DNA methylation and ATAC-seq analysis, respectively, are associated with decreased transcription, while activating histone methylation such as H3K4Me3 at promoters and open chromatin are associated with increased transcription. (E) Western blot for representative BOS (n = 5) and representative control (n = 5) fibroblast whole-cell lysate extracts shows no significant difference in total ASXL1 protein. This was repeated 3 times. (F) Western blot for representative BOS (n = 5) and representative control (n = 5). Fibroblast histone extracts showed no significant difference in H2AK119ub, H3K4me3, and H3K27me3. This was repeated 3 times.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

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