Integrating Nuclear Mechanics, Shape, and Volume with Chromatin State to Control Cell Fate Transitioning

By Stuart P. Atkinson

Early during differentiation, pluripotent colonies briefly compact and many nuclei deform while signaling proteins such as YAP and p38 light up in distinct spatial patterns — a rapid mechanical and biochemical response that helps cells sense crowding and decide their next fate. This figure captures those early nuclear shape and signaling changes and, importantly, motivates the paper’s central insight: local “crowd sensing” couples physical compression to signal transduction, which in turn feeds into an epigenetic control point that primes chromatin for coordinated cell‑fate transitions. Adapted from Fig. 1 of McCreery et al.

Ch-Ch-Ch-Ch-Changes: What Do We Know About Pluripotent Stem Cell Fate Transitions?

The differentiation of human pluripotent stem cells to specific lineages, which researchers employ as a model to study normal human embryogenesis, involves tightly coordinated alterations in gene expression and chromatin profiles alongside significant morphological and mechanical alterations. While a large body of research has described these processes in detail, we know little about how cell shape transitions and nuclear mechanical/volumetric properties influence gene expression and chromatin profiles during the lineage transitions that take place as pluripotent stem cells exit the pluripotent state and differentiate.

Removing the growth factor FGF2 triggers a rapid change in nuclear mechanics: nuclear contents move less, nuclei flatten under compression, and YAP shifts its location—early mechanical responses that precede fate changes. Adapted from Fig. 2 of McCreery et al.

To fill this knowledge gap, researchers led by Yekaterina A. Miroshnikova and Sara A. Wickstrm employed human models to define the rapid, compaction-triggered changes in nuclear shape and volume that occur during cell fate transitions and ultimately affect the chromatin landscape. Overall, this new Nature Cell Biology study uncovers a mechanism that integrates nuclear mechanics, shape, and volume with biochemical signaling and chromatin alterations to control cell fate transition dynamics (McCreery and Stubb et al.).

Paired-Tag technology from Epigenome Technologies enables simultaneous profiling of transcriptomics and epigenetics in single cells; could integrating this approach into this fascinating new study have yielded additional insights into how mechano-osmotic signaling controls chromatin state and fate transitions in human ? Paired-Tag technology from Epigenome Technologies generates joint epigenetic and transcriptomic profiles at single-cell resolution and detects histone modifications and RNA transcripts in individual nuclei with comparable efficiency to single-nucleus RNA-seq/ChIP-seq assays while avoiding the need for cell sorting.

Flattening the nucleus alters chromatin and gene activity so cells cluster into states that are more likely to differentiate, showing how shape can prime a cell’s fate. Adapted from Fig. 3 of McCreery et al.

Mechano-Osmotic Remodeling of Chromatin Architecture and Nuclear Mechanics Influence Cell-Fate Transitions

The authors demonstrated that rapid growth-factor-driven mechano-osmotic remodeling of chromatin architecture and nuclear mechanics influenced cell-fate transitions during differentiation. Overall, the removal of the pluripotency-associated growth factors required to inhibit differentiation led to rapid alterations in the mechano-osmotic state of the nucleus. These alterations induced nuclear deformation and reduced nuclear volume, thereby increasing nucleoplasm viscosity and macromolecular crowding. The authors hypothesized that the nuclear deformation induced by increased osmotic stress prompted the enhanced chromatin accessibility observed at differentiation-associated gene loci (as measured by single-cell multiome assay for transposase-accessible chromatin using sequencing and RNA sequencing). Furthermore, they stated that the associated transient and reversible chromatin remodeling did not likely suffice to facilitate cell fate conversion; instead, this epigenetic mechanism lowered the energy barrier for cell fate alterations driven by signaling factors and may even synchronize chromatin states across heterogeneous cell populations, allowing them to respond to specific signaling factors in a similar manner.

This exciting study also suggested the existence of two distinct components that triggered nuclear deformation by mechanical compression. The authors hypothesized that mechanical components triggered alterations in specific enhancer regions and subsequent transcriptional responses via mechanosensitive transcription factors, while the osmotic stress component likely triggered a transcriptional reset and chromatin remodeling. Finally, the team identified the Polycomb repressive complex 1 (PRC1)Chromobox protein homolog 2 (CBX2) axis as a mechano-osmotically sensitive chromatin regulator; a finding that agrees with previous studies that revealed how CBX2PRC1 complex components form condensates that colocalize with chromatin and relevant genes (Eeftens et al., Plys et al., and Tatavosian et al.) and the importance of condensate formation as a means to buffer cells from osmotic pressure/heat stress (Watson et al.).

Changes in osmotic pressure alter phosphorylation patterns and control CBX2 condensates, linking mechanical stress to chromatin regulators that gate gene repression. Adapted from Fig. 5 of McCreery et al.

A New Mechanism Controlling Call Fate Decisions Through Chromatin

Overall, this fascinating new pluripotent stem cell-based study describes a novel mechanism integrating nuclear mechanics, shape, and volume with biochemical signaling and chromatin state to control gene expression profiles and cell-fate transitions. These findings also further our understanding of the role of mechanochemical feedback loops; here, biochemical signals altered the mechanical properties of the nucleus to change the chromatin state of pluripotent stem cells, and extrinsic forces altered how cells interpret biochemical signals to influence cell-fate decision dynamics.

The additional integration of simultaneous profiling of transcriptomics and epigenetics in single cells, afforded by applying Paired-Tag technology from Epigenome Technologies, could have provided a more detailed description of how mechano-osmotic signaling modulates the chromatin landscape and controls the cell fate transitions that occur as human by providing a simultaneous picture of histone modification and transcriptomic profiles from the same single cell.