Ning, A. | Search bioRxiv

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↗