📰 "Chromatin remodelling enables enhancer resetting to facilitate the ERK transcriptional response"
https://www.biorxiv.org/content/10.64898/2026.03.27.714694v1?rss=1 #Extracellular #Dynamics
Chromatin remodelling enables enhancer resetting to facilitate the ERK transcriptional response
During development, cellular identity is ultimately determined by transcriptional output: lineage-specific genes must be activated, while genes associated with alternative fates must be repressed. This process depends on the activity of chromatin remodelling complexes, which regulate the accessibility of transcription factors to chromatin regulatory elements. In addition, cellular identity is shaped by exposure to intercellular signals. Understanding the mechanisms by which extracellular signals are translated into changes in the transcriptional program is essential for understanding cell fate decisions during development, as well as in disease conditions such as cancer. Here we describe a rapid and widespread enhancer resetting event in response to ERK signalling in mouse ES cells. This process occurs in two distinct phases: an immediate, genome-wide alteration in transcription factor binding dynamics at regulatory regions which is dependent on the release of paused RNA Polymerase II, followed by the re-establishment of a context appropriate, stable chromatin state. We demonstrate that the chromatin remodelling complex NuRD is required for this reestablishment phase and for the appropriate transcriptional response to ERK signalling. We propose that enhancer resetting places genomic regulatory regions in a state which is permissive to the exchange of transcription factors in order to establish a new, stable enhancer topology enabling rapid yet precise transcriptional response to extracellular signals.
### Competing Interest Statement
The authors have declared no competing interest.
Medical Research Council, https://ror.org/03x94j517, MR/R009759/1, MR/X018342/1, MR/Y000595/1, MR/P019471/1, MR/M010082/1
Wellcome Trust, https://ror.org/029chgv08, 206291/Z/17/Z, 203151/Z/16/Z
Isaac Newton Trust, 17.24(aa)
📰 "A Conserved Geometric Code: Extracellular Matrix Curvature Directs Cell Migration Strategy via Nuclear Mechanosensing"
https://www.biorxiv.org/content/10.64898/2026.03.24.713851v1?rss=1 #Extracellular #CellMigration
A Conserved Geometric Code: Extracellular Matrix Curvature Directs Cell Migration Strategy via Nuclear Mechanosensing
Cells navigate complex tissue microenvironments defined by intricate physical cues, yet how they interpret the three-dimensional geometry of the extracellular matrix (ECM) remains an open question. Current models often fail to account for the tortuous architectures found in physiological tissues. Here, we demonstrate that ECM curvature functions as a tissue-specific geometric code read by the cell nucleus. By mapping collagen architectures across cancers and tissues, we find unique curvature fingerprints preserved during metastasis. Using micro-engineered substrates, we show that high curvature imposes localized nuclear bending stress, triggering a Lamin A/C-cPLA2-Ca2+ mechanotransductive cascade. This sensor rewires the cytoskeleton from longitudinal stress fibers to a cortical actomyosin network, driving a sharp transition from fast mesenchymal migration to a slower, exploratory amoeboid phenotype. We term this "nuclear curvotaxis", establishing a physical principle linking static geometry to dynamic strategy, with implications for predicting metastatic risk, understanding immune exclusion, and designing bio-instructive scaffolds for tissue engineering.
### Competing Interest Statement
The authors have declared no competing interest.
National Natural Science Foundation of China, 12572352, 12225208, 12432015
Surface Project (Key Grant) of Chinese Medicine Education Assciation, 2024KTZ037
Technology Innovation Leading Program of Shaanxi, 2024QCY-KXJ069
Scientific Research Program Funded by Education Department of Shaanxi Provincial Government, 24JP160
📰 "Stereoselective binding of prasugrel active metabolite to the P2Y12 receptor: insights from a molecular modeling approach"
https://www.biorxiv.org/content/10.64898/2026.03.26.713933v1?rss=1 #Extracellular #Dynamics
Stereoselective binding of prasugrel active metabolite to the P2Y12 receptor: insights from a molecular modeling approach
Prasugrel is a prodrug, widely used in antiplatelet strategy for secondary prevention after acute coronary syndrome. The metabolism of prasugrel leads to the formation of the Prasugrel Active Metabolite (PAM), an irreversible P2Y12 receptor antagonist. Its mode of binding has not yet been fully established, although it is known that it binds covalently to P2Y12 by forming a disulfide bridge with cysteines and its sulfur moiety. PAM is a molecule with two chiral centers, resulting in four stereoisomers which appear to be stereoselective upon binding. A combination of different molecular modeling methods, such as molecular dynamics, ensemble docking, and Density Functional Theory (DFT), were used to rationalize these differences in antagonism observed in vitro and to elucidate the mode of binding of PAM to P2Y12. PAM is found to bind to the closed P2Y12 conformation in a preferential way. Although the four stereoisomers have comparable affinity, the location of the RS stereoisomer makes the formation of a disulfide bond with cysteines more favorable, particularly with cysteine 175. Compared to the RR stereoisomer, the RS stereoisomer interacts less deeply with the P2Y12 receptor, interacting in particular with the second and third extracellular loops, explaining the competition observed with cangrelor and an intermediate metabolite of prasugrel. Furthermore, DFT calculations have shown that the formation of a disulfide bridge is energetically more favorable with the RS stereoisomer than with the RR stereoisomer. The physical interactions and chemical reaction between the RS stereoisomer and the P2Y12 receptor are key factors in explaining the stereoselective binding of PAM to P2Y12.
### Competing Interest Statement
The authors have declared no competing interest.
SUN2 mediates epigenetic remodeling to drive mechanotransduction during skin fibrosis
Fibrosis involves sustained changes in fibroblast gene expression, leading to excessive extracellular matrix (ECM) deposition and progressive tissue stiffening. Although matrix stiffness is a potent regulator of cell fate and transcription, it is not clear how nuclear mechanosensing contributes to fibrosis. Here, we define a central role for SUN2, a component of linker of nucleoskeleton and cytoskeleton (LINC) complexes, as a mediator of stiffness-dependent nuclear and chromatin responses during skin fibrosis. SUN2 transcripts are upregulated in dermal fibroblasts of patients with systemic sclerosis and Sun2 protein is elevated in fibrotic mouse skin. Nuclear size, A-type lamins and Sun2 are elevated in dermal fibroblasts plated on stiff substrates. Loss of Sun2 protects against bleomycin-induced skin fibrosis in vivo and abolishes stiffness-induced changes in nuclear size and fibrotic gene expression in vitro. Mechanistically, we identify three Sun2 -dependent mechanosensitive chromatin states and show that mechanical induction of the histone methyltransferase Ezh2 requires Sun2 . These findings define SUN2 as a nuclear mechanosensor that couples matrix stiffness to chromatin regulation and transcriptional programs that drive fibrosis, identifying it as a potential therapeutic target pathway in fibrotic disease.
### Competing Interest Statement
The authors receive research funding from Boehringer-Ingelheim Pharmaceutical, Inc.
National Institute of Arthritis and Musculoskeletal and Skin Diseases, https://ror.org/006zn3t30, AR076938, AR0695505, AR084558, AR085488
National Institute of General Medical Sciences, https://ror.org/04q48ey07, GM153474
LEO Foundation, https://ror.org/02rgsr590
Boehringer Ingelheim (Germany), https://ror.org/00q32j219
Loss of Sun2 ablates nuclear mechanosensing-driven extracellular matrix production and mitigates lung fibrosis
Fibrosis and pathological stiffening of tissue are driven by mechanical and biochemical signaling pathways. Here, we find that Sun2, an integral inner nuclear membrane component of Linker of Nucleoskeleton and Cytoskeleton (LINC) complexes, is up-regulated in the lung of patients suffering from fibrotic conditions and in fibroblasts during an injury-induced mouse model of lung fibrosis. Sun2 protein levels also increase in primary lung fibroblasts in a substrate stiffness-dependent manner. Sun2-/- primary lung fibroblasts respond to TGFβ, become contractile, and express a key marker of extracellular matrix-producing fibroblasts, Cthrc1 . Consistent with this, Sun2 is dispensable for myofibroblast formation and repairing the alveolar barrier after bleomycin injury. Remarkably, however, fibrosis does not develop in bleomycin-treated Sun2-/- mouse lungs. This is explained by the requirement for Sun2 to up-regulate genes encoding extracellular matrix proteins. We therefore suggest that Sun2-containing LINC complexes contribute to a mechanical coincidence detection mechanism that acts in concert with canonical TGFβ signaling necessary for pathologic extracellular matrix protein production, representing a nuclear mechanosensing node for intervention in fibrotic diseases of the lung.
### Competing Interest Statement
The authors have declared no competing interest.
National Institutes of Health, F31HL158119, F31AR085488, R35GM153474, 5R01HL163984, 1R01HL178097-01A1, R01AR076938
National Institutes of Health, https://ror.org/01cwqze88, R01AR0695505, R01AR084558
Actin-membrane interface stress regulates Arp2/3-branched actin density during lamellipodial protrusion
Motile cells can sense and exert forces on the extracellular environment through dynamic actin networks. Increased stress against the polymerizing barbed ends of branched actin networks has been shown to lead to an increase in the density of these networks through a force feedback mechanism, though this phenomenon has not been explored through the examination of real-time responses of endogenous actin networks in cells. Here, we utilize mouse embryonic fibroblast CRISPR knock-in lines with labeled ARP2/3 complex to identify cellular and extracellular conditions that regulate branched actin density and enrichment at the leading edge of lamellipodial protrusions. A common theme shared among all branched actin density-increasing conditions is higher levels of interface stress between the plasma membrane and the barbed ends of the lamellipodial actin network. Among these conditions, we find that ARP2/3 is specifically required for robust spreading and protrusion in response to increased extracellular viscosity. Interestingly, time-lapse traction force microscopy of ARP2/3-dependent viscosity responses show significantly reduced changes in strain energy applied to the substrate when compared to spreading and motility through cell-matrix adhesion. In addition, we find that increased extracellular viscosity can bypass the need for extracellular matrix proteins to support lamellipodial protrusion driven by optogenetic Rac activation. Our studies provide strong support for in vitro models of branched actin force feedback responses and further characterize an essential role for branched actin in mediating dramatic cell shape changes in response to increased extracellular viscosity.
### Competing Interest Statement
The authors have declared no competing interest.
NIGMS, R35GM130312, R35GM158040, F32GM131578
📰 "Biofilm Initiation via Extracellular Matrix Production Driven by Cell Orientation Patterning in Growing Escherichia coli Populations"
https://www.biorxiv.org/content/10.64898/2026.03.26.714369v1?rss=1 #Extracellular #Pressure
Biofilm Initiation via Extracellular Matrix Production Driven by Cell Orientation Patterning in Growing Escherichia coli Populations
Unicellular microorganisms can make a transition to multicellular states that enhance survival under environmental fluctuations. In bacteria, one of these states is the biofilm, defined by the production of an extracellular matrix. Although biofilm maturation and dispersion have been extensively studied, where and how initial matrix production is induced within a growing population remains largely unknown. Here we show that production of colanic acid, an important matrix component, is initiated around topological defects, where cell orientation mismatches and growth-induced pressure builds up, in bacterial monolayers. Using Escherichia coli reporting mechanically induced production of colanic acid in response to cell contact and deformation, we found matrix production accompanied by out-of-plane growth under agar-pad confinement. Controlling confinement geometry using microfluidic devices dictated the positions of topological defects and thereby localized regions of high matrix production. These findings reveal that the cell orientation patterning spatially organizes mechanical cues to induce matrix production for biofilm initiation of bacteria.
### Competing Interest Statement
The authors have declared no competing interest.
📰 "Multidimensional Regulatory Mechanisms of Extracellular Matrix Stiffness in Breast Cancer and Its Prospects for Clinical Translation"
https://doi.org/doi:10.1016/j.clbc.2026.02.017https://pubmed.ncbi.nlm.nih.gov/41881881/ #Extracellular #Adhesion #Dynamics📰 "Aligned Fibronectin Microenvironment Temporally Facilitates Profibrotic Fibroblast Activation via Integrin α5β1"
https://doi.org/doi:10.1002/advs.202600047https://pubmed.ncbi.nlm.nih.gov/41875346/ #Mechanosensing #Extracellular
Rxiv mechanobio