Nuclear mechanosensing controls MSC osteogenic potential through HDAC epigenetic remodeling

Killaars, Anouk R.; Walker, Cierra J.; Anseth, Kristi S.

doi:10.1073/pnas.2006765117

Cited by 70 publications

(80 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Some miRNAs can have half-lives on the scale of multiple days, which motivated our formulation of 𝛼(𝑡 𝑠𝑙𝑜𝑤 ) to conceptually include these non-coding RNA molecules. More recent experiments have focused on detailed changes of chromatin organization within the nucleus, confirming that epigenetic changes occur in response to mechanical signaling (8) and highlighting the role of the LINC complex as a direct, physical mechanosensory (12,54,68). Additionally, we have recently shown that epithelial cell sheets primed on a stiff matrix for 3 days also store mechanical memory through nuclear YAP localization, which continues to enhance cell migration through enhanced pMLC expression and focal adhesion formation on soft matrix for 2-3 days (7).…”

Section: Discussionmentioning

confidence: 97%

“…Including a dependence on 𝑥 ensures that the persistence time of mechanical memory increases nonlinearly with priming time for a specified priming stiffness (6). Mechanistically, our definition of 𝑥 includes mechanosensitive epigenetic modifiers such as HDAC and HAT (8,57,58), and while the activity of these enzymes to flip epigenetic marks occurs on shorter timescales relative to memory (57), chromatin structural organization and downstream effects on transcription can be much slower due to glassy dynamics of actual chromatin conformational change (59)(60)(61). This couples the slow dynamics of the reinforcement sensitivity to the steady-state value of 𝑥, which changes depending on the specific location within each region of the phase diagram.…”

Section: Nonlinear Dynamics Of Positive Reinforcement Sensitivity Capture Full Range Of Memory Retention Outcomesmentioning

confidence: 99%

See 1 more Smart Citation

Dynamic Self-Reinforcement of Gene Expression Determines Acquisition and Retention of Cellular Mechanical Memory

Price

Mathur

et al. 2021

Preprint

View full text Add to dashboard Cite

Mechanotransduction describes activation of gene expression by changes in the cell's physical microenvironment. Recent experiments show that mechanotransduction can lead to long-term "mechanical memory", where cells cultured on stiff substrates for sufficient time (priming phase) maintain altered phenotype after switching to soft substrates (dissipation phase), as compared to unprimed controls. The timescale of memory acquisition and retention is orders of magnitude larger than the timescale of mechanosensitive cellular signaling, and memory retention time changes continuously with priming time. We develop a model that captures these features by accounting for positive reinforcement in mechanical signaling. The sensitivity of reinforcement represents the dynamic transcriptional state of the cell composed of protein lifetimes and 3D chromatin organization. Our model provides a single framework connecting microenvironment mechanical history to cellular outcomes ranging from no memory to terminal differentiation. Predicting cellular memory of environmental changes can help engineer cellular dynamics through changes in culture environments.

show abstract

Section: Discussionmentioning

confidence: 97%

Section: Nonlinear Dynamics Of Positive Reinforcement Sensitivity Capture Full Range Of Memory Retention Outcomesmentioning

confidence: 99%

Dynamic Self-Reinforcement of Gene Expression Determines Acquisition and Retention of Cellular Mechanical Memory

Price

Mathur

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Topographic cues act as epigenetic modifiers, leading to widespread changes in histone acetylation and methylation [51]. Using photoconvertible (photo-softening [52], photo-stiffening [53]) hydrogels, researchers have shown that human mesenchymal stem cells grown on stiff matrices undergo chromatin remodeling that is manifest in increased histone acetyltransferase (HAT) and reduced histone deacetylase (HDAC) levels. These changes require an intact LINC complex, reinforcing the notion that nucleo-cytoskeletal coupling is essential for chromatin remodeling [52,53] and correlates with increased acetylated chromatin and YAP nuclear localization.…”

Section: Chromatin Landscape Is Modulated By Mechanical Stimulimentioning

confidence: 99%

“…Using photoconvertible (photo-softening [52], photo-stiffening [53]) hydrogels, researchers have shown that human mesenchymal stem cells grown on stiff matrices undergo chromatin remodeling that is manifest in increased histone acetyltransferase (HAT) and reduced histone deacetylase (HDAC) levels. These changes require an intact LINC complex, reinforcing the notion that nucleo-cytoskeletal coupling is essential for chromatin remodeling [52,53] and correlates with increased acetylated chromatin and YAP nuclear localization. Interestingly, upon chronic culture on stiff substrates, cells are unable to remodel their nuclear architecture in response to photosoftening, underscoring the importance of physiological stiffness for cell culture [52].…”

Section: Chromatin Landscape Is Modulated By Mechanical Stimulimentioning

confidence: 99%

Mechanical Regulation of Transcription: Recent Advances

Wagh

Ishikawa

Garcia

et al. 2021

Trends in Cell Biology

View full text Add to dashboard Cite

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...

show abstract

“…The gene regulation hypothesis claims that the mutations or defects in LINC components or Lamin/Emerin lead to a severe dysregulation of gene expression [227]. Consequently, cellular physiology is dysregulated, impairing, e.g., stem cell differentiation, and thus resulting in the clinical disease manifestations such as premature aging or muscle weakness [228]. Contrary to this, the structural hypothesis states that nuclear deformation and fragility caused by the mutations is the most important step in the disease process.…”

Section: The Gist Of the Matter: Nuclear Mechanotransductionmentioning

confidence: 99%

From the Matrix to the Nucleus and Back: Mechanobiology in the Light of Health, Pathologies, and Regeneration of Oral Periodontal Tissues

et al. 2021

View full text Add to dashboard Cite

Among oral tissues, the periodontium is permanently subjected to mechanical forces resulting from chewing, mastication, or orthodontic appliances. Molecularly, these movements induce a series of subsequent signaling processes, which are embedded in the biological concept of cellular mechanotransduction (MT). Cell and tissue structures, ranging from the extracellular matrix (ECM) to the plasma membrane, the cytosol and the nucleus, are involved in MT. Dysregulation of the diverse, fine-tuned interaction of molecular players responsible for transmitting biophysical environmental information into the cell’s inner milieu can lead to and promote serious diseases, such as periodontitis or oral squamous cell carcinoma (OSCC). Therefore, periodontal integrity and regeneration is highly dependent on the proper integration and regulation of mechanobiological signals in the context of cell behavior. Recent experimental findings have increased the understanding of classical cellular mechanosensing mechanisms by both integrating exogenic factors such as bacterial gingipain proteases and newly discovered cell-inherent functions of mechanoresponsive co-transcriptional regulators such as the Yes-associated protein 1 (YAP1) or the nuclear cytoskeleton. Regarding periodontal MT research, this review offers insights into the current trends and open aspects. Concerning oral regenerative medicine or weakening of periodontal tissue diseases, perspectives on future applications of mechanobiological principles are discussed.

show abstract

Nuclear mechanosensing controls MSC osteogenic potential through HDAC epigenetic remodeling

Cited by 70 publications

References 57 publications

Dynamic Self-Reinforcement of Gene Expression Determines Acquisition and Retention of Cellular Mechanical Memory

Dynamic Self-Reinforcement of Gene Expression Determines Acquisition and Retention of Cellular Mechanical Memory

Mechanical Regulation of Transcription: Recent Advances

From the Matrix to the Nucleus and Back: Mechanobiology in the Light of Health, Pathologies, and Regeneration of Oral Periodontal Tissues

Contact Info

Product

Resources

About