Wurmser, A. A. M. | Search bioRxiv

bioRxiv2026

WNT/β-catenin increases 3D chromatin mobility and reorganisation during posterior cell state transitions

Chromatin mobility, the exploration of 3D conformations by the chromatin fibre, is implicated in transcription and DNA repair, and is thought to decrease progressively as cells differentiate. Here, combining live-cell 3D single-nucleosome tracking with genomic approaches, we show that chromatin mobility instead changes in a cell-type-specific manner, increasing as pluripotent cells acquire posterior fates. This is accompanied by 3D genome reorganisation, including loss of Polycomb-associated interactions and emergence of CDX2-associated interactions. Withdrawal of posteriorising WNT/{beta}-catenin signalling rapidly reduces chromatin mobility and partially restores Polycomb-associated chromatin interactions, while Cdx1/2/4-null cells fail to acquire these WNT/{beta}-catenin-dependent changes. Together, our findings establish chromatin mobility as a regulated property of cell state, with WNT/{beta}-catenin signalling and CDX factors acting as mediators that fine-tune the sampling of 3D chromatin interactions during cell state transitions.

cell biology↗

bioRxiv2026

Organoids reveal niche-specific mechanotransduction-guided human cortical patterning and cell fate acquisition

The highly dynamic mechanical environment of the developing cerebral cortex has the potential to encode information vital for neuronal differentiation. Changes in local biophysical properties have been implicated in processes ranging from the maintenance of neural progenitors to long-range axon guidance. However, whether cortical mechanics influence cellular organisation and specification during neurogenesis remains largely unexplored. Here, we leverage a 3D mosaic organoid model of human cortical development, in which we selectively disrupt a key component of nuclear mechanosensing, the LINC complex, decoupling cells from their mechanical environment. We show that LINC-decoupling alters nuclear morphology in a compartment-specific manner, driving preferential exclusion from the germinal zone and concomitant premature differentiation. Excluded cells exhibit a biased spatial distribution in the cortical plate and altered fate allocation, with loss of intermediate progenitors and upper-layer neuron populations. Combining this approach with single-cell transcriptomic profiling, we reveal a signature of impaired ERK activation and density sensing in LINC-decoupled cells. Furthermore, we show that altered density sensing contributes to mislocalisation of the nuclear envelope protein emerin and disruption of histone mark deposition during differentiation. Taken together, our findings illustrate how the dynamic mechanical environment of a complex tissue can dictate cell fate and pattern formation during development.

developmental biology↗