Mechanical Regulation of Transcription: Recent Advances

Abstract

Mechanotransduction is the ability of a cell to sense mechanical cues from its microenvironment and convert them into biochemical signals to elicit adaptive transcriptional and other cellular responses. Here, we describe recent advances in the field of mechanical regulation of transcription, highlight mechanical regulation of the epigenome as a key novel aspect of mechanotransduction, and describe recent technological advances that could further elucidate the link between mechanical stimuli and gene expression. In this review, we emphasize the importance of mechanotransduction as one of the governing principles of cancer progression, underscoring the need to conduct further studies of the molecular mechanisms involved in sensing mechanical cues and coordinating transcriptional responses. Cells and Tissues Respond to the Physical EnvironmentCells in the human body are subject to a wide variety of mechanical stimuli acting at multiple scales. At the single molecule level, receptors on immune cells such as T and B cells leverage force to discriminate between ligands, enabling efficient recognition of antigen [1]. At the singlecell level, mechanical cues guide cell fate decisions in stem cells [2] and migration strategies of cancer cells [3]. Matrix stiffness alters the force generation capability of cancer cells, which scales with metastatic potential [4]. Finally, collective processes such as wound healing, tumorigenesis, and tissue homeostasis are intimately linked with the physical microenvironment [5,6]. In order to engage in functional responses appropriate to both passive mechanical stimuli, such as stiffness or topographic features of the cellular environment, and active ones, such as forces generated by cells and tissues, cells must be able to sense and measure mechanical perturbations. Different elements of the cell act in concert to maintain structural integrity and coordinate cellular sensing of external forces and mechanical stimuli. These stimuli are subsequently transmitted to the nucleus leading to broad changes in chromatin structure and accessibility (Figure 1, Key Figure) [7]. While we have come to appreciate the role of mechanical forces in shaping the genome, the molecular mechanisms involved in mechanotransduction (see Glossary) remain an enigma, with potential long-term implications for physiology, disease, and therapeutics. The focus of this review is to highlight recent advances in understanding the interplay between mechanosensing and transcription, with a particular emphasis on tumorigenesis and cancer progression (Figure 1). The Cellular Mechanosensing ApparatusThe structural mechanosensing machinery can be broadly classified into two groups: (i) proximal mechanosensing apparatus consisting of cell surface receptors, focal adhesion (FA) complexes, cell-cell junctions, and the actomyosin cytoskeleton, and (ii) proteins of the nuclear envelope. In adherent cells, integrins link the cell to the extracellular matrix (ECM) through FAs (Figure 2). Under applied forces, integrins undergo conforma...

Characterization of primary models of human trophoblast

“…Others have also demonstrated the importance of tissue/mechanical stiffness in regulating miRNAs that target cytoskeletal, adhesive and extracellular matrix proteins (Moro et al, 2019). Therefore, we reason that mechanical cues (Wagh et al, 2021) are affecting HLA transcription and expression.…”

The Phenotypic Responses of Vascular Smooth Muscle Cells Exposed to Mechanical Cues

“…Recent studies using single-cell transcriptomics have demonstrated SMC heterogeneity in healthy and diseased arteries [ 107 , 108 , 109 ]. New transcriptomic analyses that integrate the in vitro models of mechanical forces are needed to unmask the potential mechanotransduction pathways beyond changes in the contractile machinery [ 110 ]. Furthermore, the determination of the phenotypic status of the SMCs must not rely exclusively on the assessment of transcriptomic changes.…”

Arp2/3 complex activity is necessary for mouse ESC differentiation, times formative pluripotency, and enables lineage specification

“…Our observations, compared with previous findings that activity of formins but not Arp2/3 complex is necessary for EMT and the assembly of unbranched contractile actin filaments (Li et al, 2010;Jurmeister et al, 2012;Rana et al, 2018), indicate that these different classes of actin nucleators and the architectures they generate have selective roles in distinct types of epithelial plasticity. With known functions in migration (Suraneni et al, 2012;Arnold 2008) and adherens junction tension (Verma et al, 2012;Fierro-Gonzales et al, 2012), there are abundant potential mechanisms whereby Arp2/3 complex activity might regulate mESC pluripotency transition (Rotty et al, 2013;Pieters and van Roy, 2014;Wagh et al, 2021;Molé et al, 2021). Our study provides a step toward closing the gap between phenotype and genotype, opening new directions and advancing new approaches to understand how morphological changes and actin filament dynamics promote pluripotency transition, with potential value for additional approaches in directing differentiations for regenerative medicine.…”