Similar Datasets
Project description:We performed genome-wide chromatin accessibility analysis using data obtained from ATAC-seq of BOS patient and control individual fibroblast samples to dissect the chromatin regulating effects of truncating ASXL1 mutations. We performed genome-wide chromatin accessibility analysis using data obtained from ATAC-seq of BOS patient and control individual fibroblast samples.
2023-04-27 | GSE230688 | GEO
Project description:We performed genome-wide analysis of protein-DNA binding using data obtained from CUT&RUN of BOS patient and control individual fibroblast samples to dissect the effects of truncating ASXL1 mutations. We performed genome-wide analysis of protein-DNA binding using data obtained from CUT&RUN of BOS patient and control individual fibroblast samples.
2023-04-27 | GSE230695 | GEO
Project description:We performed gene expression profiling analysis using data obtained from RNA-seq of BOS patient and control individual fibroblast samples to dissect the transcriptomic effects of truncating ASXL1 mutations. We performed gene expression profiling analysis using data obtained from RNA-seq of BOS patient and control individual fibroblast samples.
2023-04-27 | GSE230686 | GEO
Project description:We performed gene expression profiling analysis using data obtained from RNA-seq of BOS patient and control individual blood samples to dissect the transcriptomic effects of truncating ASXL1 mutations. We performed gene expression profiling analysis using data obtained from RNA-seq of BOS patient and control individual blood samples.
2023-04-27 | GSE230685 | GEO
Project description:Mutations in genes associated with chromatin remodeling, such as Additional sex combs-like 1 (ASXL1), underlie a spectrum of congenital abnormalities and neurodevelopmental disorders. Pathogenic variants in ASXL1 are classically associated with Bohring–Opitz syndrome (BOS), a severe developmental disorder caused predominantly by de novo truncating mutations. In this study, we present a 14-year-old female with overgrowth, macrocephaly, and normal neurodevelopment, features that diverge from the typical BOS phenotype. This proband was found to carry a paternally-inherited ASXL1 missense mutation (c.4562C>T p.Ala1521Val) in the plant homeodomain (PHD), a variant of unknown significance (VUS). To investigate its functional impact, we performed integrated transcriptomic (RNA-seq) and metabolomic profiling of peripheral blood and patient-derived fibroblasts, with comparison to unaffected controls and previously characterized BOS samples. Transcriptomic analysis demonstrated that ASXL1 missense carriers exhibit a gene expression profile distinct from BOS. Cross-tissue integration identified 104 shared differentially expressed genes, significantly enriched for oxidative phosphorylation pathways. Notably, mitochondrial genes were downregulated in blood but upregulated in fibroblasts, suggesting tissue-specific metabolic adaptation. Metabolomic profiling revealed depletion of glycolytic intermediates and reduced levels of key energy carriers, including NAD⁺ and NADPH, indicating impaired energy metabolism. In contrast to BOS, which is characterized by transcriptional de-repression and increased glycolytic activity, ASXL1 missense cells demonstrated a predominantly repressive transcriptional profile and diminished bioenergetic capacity. These findings define a distinct molecular and metabolic signature associated with ASXL1 missense variation and support an expanded phenotypic spectrum beyond classical BOS.
2026-07-11 | GSE337807 | GEO
Project description:Bohring-Opitz syndrome (BOS, OMIM#605309) is a rare neurodevelopmental disorder caused by heterozygous and truncating variants in ASXL1 (Additional Sex Combs Like 1), a chromatin-associated epigenetic regulator that forms the catalytic PR-DUB complex with BAP1. Truncating ASXL1 variants are also recurrent somatic drivers in myeloid leukemia, yet the metabolic consequences of these mutations remain undefined. Using patient derived dermal fibroblasts, we show that truncating ASXL1 variants drive a Warburg-like metabolic state characterized by increased glycolytic flux, and accumulation of pyruvate and lactate. Stable isotope tracing revealed preservation of glucose-derived carbon incorporation into tricarboxylic acid (TCA) cycle intermediates, suggesting compensatory metabolic adaptation to maintain pyruvate-dependent TCA cycle metabolism. Overexpression of truncating ASXL1 constructs in cell models replicated this phenotype. Mechanistically, truncated ASXL1 shows decreased occupancy at an H3K4me3-marked enhancer upstream of mitochondrial pyruvate carrier 2 (MPC2), together with BAP1 co-recruitment, and selectively reduces MPC1 and MPC2 protein levels through a mechanism that is independent of transcript levels. Pharmacologic inhibition of the MPC reproduces both the metabolic and Wnt signaling phenotypes of BOS cells, while canonical Wnt activation also increases glycolytic flux but without reducing the MPC abundance, implicating that reduced MPC abundance acts upstream of signaling dysregulation. These findings define a previously unrecognized pathway connecting gain-of-function ASXL1 truncation to chromatin-level regulation of mitochondrial pyruvate transport, and identify the MPC as a central mediator of epigenetic-metabolic crosstalk in both a rare developmental syndrome and ASXL1-mutated myeloid malignancies.
2026-07-14 | GSE337675 | GEO
Project description:De novo ASXL1 mutations are found in patients with Bohring-Opitz syndrome (BOS), a disease with severe developmental defects and early childhood fatality. The underlying pathologic mechanisms remain largely unknown. Using Asxl1-targeted murine models, we found that Asxl1 global loss or conditional deletion in osteoblasts and their progenitors in mice leads to significant bone loss and markedly decreased numbers of marrow mesenchymal stem/progenitor cells (MSPCs) compared with wild-type (WT) littermates. Asxl1 null MSPCs display impaired self-renewal and skewed differentiation from osteoblasts towards adipocytes. ChIP-seq data identified that ASXL1 and H3K4me3 co-occupy the promoter regions of genes critical for MSPC self-renewal. Loss of Asxl1 diminished the genome enrichment of H3K4me3. Combined analysis of RNA-seq and ChIP-seq data revealed that Asxl1 loss in MSPCs altered the expression of ASXL1/H3K4me3 target genes controlling self-renewal/lineage commitment. Our study unveil a pivotal role of ASXL1 in H3K4me3-associated bone homeostasis
2018-12-08 | GSE75786 | GEO
Project description:Whole exome sequencing (WES) files of a patient suffering from a combined immunodeficiency, and his parents.
2014-10-31 | E-MTAB-2962 | biostudies-arrayexpress