Article

Biophysical Regulation of Histone Acetylation in Mesenchymal Stem Cells

Bioengineering College, Chongqing University, Chongqing, China.
Biophysical Journal (Impact Factor: 3.97). 04/2011; 100(8):1902-9. DOI: 10.1016/j.bpj.2011.03.008
Source: PubMed

ABSTRACT

Histone deacetylation and acetylation are catalyzed by histone deacetylase (HDAC) and histone acetyltransferase, respectively, which play important roles in the regulation of chromatin remodeling, gene expression, and cell functions. However, whether and how biophysical cues modulate HDAC activity and histone acetylation is not well understood. Here, we tested the hypothesis that microtopographic patterning and mechanical strain on the substrate regulate nuclear shape, HDAC activity, and histone acetylation. Bone marrow mesenchymal stem cells (MSCs) were cultured on elastic membranes patterned with parallel microgrooves 10 μm wide that kept MSCs aligned along the axis of the grooves. Compared with MSCs on an unpatterned substrate, MSCs on microgrooves had elongated nuclear shape, a decrease in HDAC activity, and an increase of histone acetylation. To investigate anisotropic mechanical sensing by MSCs, cells on the elastic micropatterned membranes were subjected to static uniaxial mechanical compression or stretch in the direction parallel or perpendicular to the microgrooves. Among the four types of loads, compression or stretch perpendicular to the microgrooves caused a decrease in HDAC activity, accompanied by the increase in histone acetylation and slight changes of nuclear shape. Knocking down nuclear matrix protein lamin A/C abolished mechanical strain-induced changes in HDAC activity. These results demonstrate that micropattern and mechanical strain on the substrate can modulate nuclear shape, HDAC activity, and histone acetylation in an anisotropic manner and that nuclear matrix mediates mechanotransduction. These findings reveal a new mechanism, to our knowledge, by which extracellular biophysical signals are translated into biochemical signaling events in the nucleus, and they will have significant impact in the area of mechanobiology and mechanotransduction.

Download full-text

Full-text

Available from: Xian Li, May 01, 2014
  • Source
    • "This reinforcement leads to decreased deflection to future mechanical stimuli, decreasing cellular sensitivity. While our data do not specifically connect acetylation with deflection, other groups have reported physical stimuli decreased HDAC6 activity and increased acetylation (Geiger et al., 2009; Li et al., 2011). Acetylation of tubulin has been implicated in microtubule stiffness (Felgner et al., 1996; Hawkins et al., 2013) and our results corroborate this. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mechanosensation is crucial for cells to sense and respond to mechanical signals within their local environment. While adaptation allows a sensor to be conditioned by stimuli within the environment and enables its operation in a wide range of stimuli intensities, the mechanisms behind adaptation remain controversial in even the most extensively studied mechanosensor, bacterial mechanosensitive channels. Primary cilia are ubiquitous sensory organelles. They have emerged as mechanosensors across diverse tissues, including kidney, liver and the embryonic node, and deflect with mechanical stimuli. Here, we show that both mechanical and chemical stimuli can alter cilium stiffness. We found that exposure to flow stiffens the cilium, which deflects less in response to subsequent exposures to flow. We also found that through a process involving acetylation, the cell can biochemically regulate cilium stiffness. Finally, we show that this altered stiffness directly affects the responsiveness of the cell to mechanical signals. These results demonstrate a potential mechanism through which the cell can regulate its mechanosensing apparatus.
    Preview · Article · Nov 2015 · Biology Open
  • Source
    • "Histone acetylation and deacetylation are critical to the modification of chromatin structure associated with the regulation of gene expression (21). Acetylation and deacetylation is involved in various developmental processes, including heart development. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The aim of the present study was to investigate the effects of Islet-1 on the process of mesenchymal stem cell (MSC) differentiation into cardiomyocyte-like cells and to elucidate the possible mechanisms involved. Lentiviral vectors expressing Islet-1 (Lenti-Islet-1) were constructed and used for C3H10T1/2 cell transfection. Cell morphology was observed. Cardiac-related genes and proteins were detected by qPCR and western blot analysis. Epigallocatechin gallate (EGCG) was used as an inhibitor of acetylated histone H3 (AcH3). AcH3 was detected by chromatin immunoprecipitation. Cells overexpressing Islet-1 tended to change into fibroblast-like cells and were arranged in the same direction. The enhanced expression of GATA binding protein 4 (Gata4), NK2 homeobox 5 (Nkx2.5), myocyte enhancer factor 2C (Mef2c) and cardiac troponin T (cTnT) was observed in the cells overexpressing Islet-1 following transfection with Lenti-Islet-1. However, the expression of hepatocyte-, bone- and neuronal-specific markers was not affected by Islet-1. The AcH3 relative amount increased following transfection with Lenti-Islet-1, which was associated with the enhanced expression of Gata4, Nkx2.5 and Mef2c in these cells. The expression of Gata4, Nkx2.5 and Mef2c in the C3H10T1/2 cells transfected with Lenti-Islet-1 and treated with EGCG was reduced following treatment with EGCG. The data presented in this study indicate that Islet-1 specifically induces the differentiation of C3H10T1/2 cells into cardiomyocyte-like cells, and one of the mechanisms involved is the regulation of histone acetylation.
    Full-text · Article · Mar 2014 · International Journal of Molecular Medicine
  • Source
    • "The results of these morphological studies suggest that the smaller 10 lm microgrooves were more effective in orienting VSC actin cytoskeleton and membrane protrusion parallel to the pattern direction. This result is consistent with previously reported results with other cell types cultured on similarly dimensioned microgroove surfaces [9] [13] [16]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Multipotent vascular stem cells have been implicated in vascular disease and in tissue remodeling post therapeutic intervention. Hyper-proliferation and calcified extracellular matrix deposition of VSC causes blood vessel narrowing and plaque hardening thereby increasing the risk of myocardial infarct. In this study, to optimize the surface design of vascular implants, we determined whether micropatterned polymer surfaces can modulate VSC differentiation and calcified matrix deposition. Undifferentiated rat VSC were cultured on microgrooved surfaces of varied groove widths, and on micropost surfaces. 10 μm microgrooved surfaces elongated VSC and decreased cell proliferation. However, microgrooved surfaces did not attenuate calcified extracellular matrix deposition by VSC cultured in osteogenic media conditions. In contrast, VSC cultured on micropost surfaces assumed a dendritic morphology, were significantly less proliferative, and deposited minimal calcified extracellular matrix. These results have significant implications for optimizing the design of cardiovascular implant surfaces.
    Full-text · Article · Feb 2014 · Biochemical and Biophysical Research Communications
Show more