Biology subjects

Ning, A.

Publications and source records attributed to Ning, A..

3 recordsLinked to original sources

bioRxiv2026

Truncating ASXL1 variants rewire cellular metabolism via mitochondrial pyruvate carrier repression

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. Truncated ASXL1 and BAP1 show aberrant co-occupancy at an H3K4me3-marked intronic regulatory element within MPC2 intron 1, with broadened ASXL1 occupancy extending beyond BRD4-defined regulatory boundaries while BRD4 positioning remains unchanged, consistent with aberrant PR-DUB complex spreading beyond its normally constrained chromatin territory. This altered occupancy is accompanied by modest but significant reduction in MPC2 transcript abundance and a disproportionately larger reduction in MPC1 and MPC2 protein levels, indicating that transcriptional dysregulation at this intronic element is amplified at the protein level through post-transcriptional mechanisms including impaired MPC1/MPC2 heterodimer stability. Pharmacologic MPC inhibition recapitulates both the metabolic and Wnt signaling phenotypes of BOS cells, while canonical Wnt activation increases glycolytic flux without reducing MPC abundance, establishing mitochondrial pyruvate restriction as causally upstream of signaling dysregulation. These findings define a previously unrecognized chromatin-to-metabolism axis connecting gain-of-function ASXL1 truncation to mitochondrial pyruvate transport, identifying MPC as a central mediator of epigenetic-metabolic crosstalk in both a rare developmental syndrome and ASXL1-mutant myeloid malignancy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=129 SRC="FIGDIR/small/737346v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1d6ee4org.highwire.dtl.DTLVardef@5b6e15org.highwire.dtl.DTLVardef@9849cforg.highwire.dtl.DTLVardef@15ebb5_HPS_FORMAT_FIGEXP M_FIG C_FIG Truncating and heterozygous ASXL1 variants cause a neurodevelopmental syndrome called Bohring-Opitz syndrome. (1) At an epigenetic level, we have shown that Truncating ASXL1 variants drive more open chromatin and aberrant activation of key developmental pathways. (2) Truncating ASXL1 mutations are sufficient to drive Decreased MPC1 and MPC2 protein levels. (3) Decreased MPC1 or MPC2 level or function are sufficient to drive increased glycolysis which is observed in BOS cells. (4) Truncating ASXL1 mutations drive Increased Wnt signaling via MPC depletion. * Increased Wnt signaling (4) is also sufficient to drive increased glycolysis (3), however Increased Wnt signaling does not drive Decreased MPC1 and MPC2 levels (2).

genetics↗

bioRxiv2025

Sequence-encoded interactions program internal condensate architecture

Many cellular condensates, such as the nucleolus and stress granules, contain multiple coexisting phases with distinct compositions and material properties. This internal organization is crucial for function, yet how it is established remains unclear. Here, using a programmable DNA system, we reveal how molecular interactions can precisely encode multiphase architecture. We find that phase separation drives macromolecules into a semi-dilute regime where subtle differences in homotypic interaction energies are amplified into dominant organizational forces. A critical interaction energy threshold must be overcome to trigger internal demixing, after which molecular partitioning scales near-linearly with interaction strength. This universal relationship is captured by an associative polymer model, and enables engineering of condensates with up to four coexisting phases exhibiting 100-fold differences in viscosity within the same droplet. These design principles extend to RNA-peptide systems, establishing a general framework for how sequence can program hierarchical self-assembly and organize biological matter.

biophysics↗

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↗