Biology subjects

ZHAO, W.

Publications and source records attributed to ZHAO, W..

4 recordsLinked to original sources

bioRxiv2025

Acute chromatin decompaction stiffens the nucleus as revealed by nanopillar-induced nuclear deformation in cells

Chromatin architecture is critical in determining nuclear mechanics. Most studies focus on the mechanical rigidity conferred by chromatin compaction from densely packed heterochromatin, but less is known on how transient changes in chromatin decompaction state impinge on nucleus stiffness. Here, we used an array of vertically aligned nanopillars to study nuclear deformability in situ after chromatin decompaction in cells. The nucleus significantly stiffened within 4 hours of chromatin decompaction but softened at longer timescales. This acute nucleus stiffening was predominantly underlied by an increase in nucleus volume, nuclear import and partially enhanced by lamin protein recruitment to the nuclear periphery. The coupling between nucleus stiffening and acute chromatin decompaction was observed in cancer cell lines with lower malignancy (e.g. MCF7, PEO1, A549) but weakened in those with higher metastatic potential (e.g. MDA-MB-231, HEYA8, HT1080), which was found to be associated with the capacity to efficiently compact heterochromatin into foci that sustains nucleus deformability required for confined migration. Our work signals how a rapid chromatin remodeling is a physiologically relevant pathway to modulate nucleus mechanics and cell migration behavior. STATEMENT OF SIGNIFICANCEMany cell processes such as wound healing, immune activation and DNA damage repair require a decompact and accessible chromatin structure. Whether such short-term remodeling of the chromatin impacts nucleus mechanics and function is poorly defined. Using nanopillars that allow interrogation of nucleus rigidity within intact cells, we showed that contrary to conventional knowledge the nucleus becomes less deformable and more rigid when chromatin is acutely decompacted due to enhanced nuclear import and swelling of the nucleus. In cancer cells, the coupling of transient chromatin decompaction to nucleus rigidity is weakened and appears to be countered by heterochromatin formation and compaction. We demonstrate here how short-term chromatin remodeling can impact nucleus and cellular properties in a time-dependent and non-genetic manner.

bioengineering↗

bioRxiv2024

Coaching ribosome biogenesis from the nuclear periphery

Severe invagination of the nuclear envelope is a hallmark of cancers, aging, neurodegeneration, and infections. However, the outcomes of nuclear invagination remain unclear. This work identified a new function of nuclear invagination: regulating ribosome biogenesis. With expansion microscopy, we observed frequent physical contact between nuclear invaginations and nucleoli. Surprisingly, the higher the invagination curvature, the more ribosomal RNA and pre-ribosomes are made in the contacted nucleolus. By growing cells on nanopillars that generate nuclear invaginations with desired curvatures, we can increase and decrease ribosome biogenesis. Based on this causation, we repressed the ribosome levels in breast cancer and progeria cells by growing cells on low-curvature nanopillars, indicating that overactivated ribosome biogenesis can be rescued by reshaping nuclei. Mechanistically, high-curvature nuclear invaginations reduce heterochromatin and enrich nuclear pore complexes, which promote ribosome biogenesis. We anticipate that our findings will serve as a foundation for further studies on nuclear deformation. HighlightsNuclear invaginations regulate ribosome biogenesis by physically contacting nucleoli. High-curvature nuclear tunnels increase ribosome biogenesis. Nanopillars reduce ribosome biogenesis by transforming high-curvature nuclear invaginations to low-curvature ones.

cell biology↗

bioRxiv2024

Membrane curvature catalyzes actin nucleation through nano-scale condensation of N-WASP-FBP17

Actin remodeling is spatiotemporally regulated by surface topographical cues on the membrane for signaling across diverse biological processes. Yet, the mechanism dynamic membrane curvature prompts quick actin cytoskeletal changes in signaling remain elusive. Leveraging the precision of nanolithography to control membrane curvature, we reconstructed catalytic reactions from the detection of nano-scale curvature by sensing molecules to the initiation of actin polymerization, which is challenging to study quantitatively in living cells. We show that this process occurs via topographical signal-triggered condensation and activation of the actin nucleation-promoting factor (NPF), Neuronal Wiskott-Aldrich Syndrome protein (N-WASP), which is orchestrated by curvature-sensing BAR-domain protein FBP17. Such N-WASP activation is fine-tuned by optimizing FBP17 to N-WASP stoichiometry over different curvature radii, allowing a curvature-guided macromolecular assembly pattern for polymerizing actin network locally. Our findings shed light on the intricate relationship between changes in curvature and actin remodeling via spatiotemporal regulation of NPF/BAR complex condensation.

molecular biology↗

bioRxiv2024

Hist2Cell: Deciphering Fine-grained Cellular Architectures from Histology Images

Histology images, with low cost, are unleashing great power of predicting cellular phenotypes in tissue, thanks to the emerging spatial transcriptomics serving as annotations. Recent efforts aimed to predict individual gene expression, suffering from low accuracy and high variability, while no methods are tailored to predict fine-grained transcriptional cell types -the most critical phenotype. Here, we present Hist2Cell, a Vision Graph-Transformer framework, to accurately resolve fine-grained transcriptional cell types (up to 40 cell types) directly from histology images and further create cellular maps of diverse tissues at a customizable resolution. Specifically, trained on human lung and breast cancer spatial transcriptome datasets, Hist2Cell accurately predicts the abundance of each cell type across space in new patient samples with Pearson Correlation Coefficient of biological informative cell types over 0.80, and effectively capturing their colocalization directly from histology images. Moreover, without re-training, it robustly generalizes to large-scale histology cancer cohorts from TCGA, highlighting recurrent cell co-localization and supporting precise survival prediction by revealing distinct tissue micro-environments and insightful cell type-patient mortality relationship. Therefore, Hist2Cell enables cost-efficient histology analysis for large-scale studies of spatial biology and precise cancer prognosis in real-world clinical diagnostics.

bioengineering↗