Mechanostimulation Promotes Nuclear and Epigenetic Changes in Oligodendrocytes

Abstract

Oligodendrocyte progenitors respond to biophysical or mechanical signals, and it has been reported that mechanostimulation modulates cell proliferation, migration, and differentiation. Here we report the effect of three mechanical stimuli on mouse oligodendrocyte progenitor differentiation and identify the molecular components of the linker of nucleoskeleton and cytoskeleton (LINC) complex (i.e., SYNE1) as transducers of mechanical signals to the nucleus, where they modulate the deposition of repressive histone marks and heterochromatin formation. The expression levels of LINC components increased during progenitor differentiation and silencing the Syne1 gene resulted in aberrant histone marks deposition, chromatin reorganization and impaired myelination. We conclude that spatial constraints, via the actin cytoskeleton and LINC complex, mediate nuclear changes in oligodendrocyte progenitors that favor a default pathway of differentiation.

Epigenetic control of oligodendrocyte development: adding new players to old keepers

“…How are mechanical signals translated into changes in gene expression? One potential mechanism is that mechanical signals modulate the actin cytoskeleton and nuclear structure of oligodendrocytes [38]. This mechanotransduction involves direct force transition from the cytoplasmic membrane to the nucleus via linker of the nucleoskeleton and cytoskeleton complex (LINC) signals, and also results in deposition of repressive histone marks [38], suggesting a direct interplay of mechanical forces with epigenetic machinery.…”

The environment rules: spatiotemporal regulation of oligodendrocyte differentiation

“…Recent work has shown that certain protein structures that connect the cell membrane to nuclear components may be at play. Researchers knocked down the expression of Syne1 (synaptic nuclear envelope protein 1), a component of the Linker of the Nucleoskeleton and the Cytoskeleton (LINC) complex, and found that increased spatial constraints, via addition of polystyrene beads or membrane compression, no longer promoted differentiation [54]. They also saw that when wild type OPCs were spatially constrained a complete reorganization of nuclear chromatin structure was observed.…”

Modulation of Oligodendrocyte Differentiation by Mechanotransduction

“…It was recently demonstrated in OLs that compressive forces—either mechanically-driven or due to spatial constraints caused by high cell density or the presence of beads of equivalent size—affect nuclear architecture and chromatin modifications (Figure 2B), causing increased heterochromatic cellular content (Hernandez et al, 2016)—namely increased trimethylated lysine-9 residues of histone-3 (H3K9me), an epigenetic modification associated with OL differentiation and maturation in vitro (Douvaras et al, 2016) and in vivo (Liu et al, 2012). Concomitantly, increased expression of myelin markers—MBP, CNP and MAG—and axonal myelination were observed.…”

“…Although interactions at the interface between cells or between cells and the extracellular environment (reviewed in Sun et al, 2012; Huveneers and de Rooij, 2013) are at the origin of mechanotransduction signaling, it is known that such stimuli propagate through the cytoskeleton and the linker of nucleoskeleton and cytoskeleton (LINC) complex to the nucleus (Figure 2A), affecting nuclear and chromosomal architecture (Mehta et al, 2010), chromatin modulation (Iyer et al, 2012; Heo et al, 2015; Hernandez et al, 2016) and gene expression (Maier et al, 2008). The discovery of substrate stiffness- and cell shape-responsive transcription factors like YAP/TAZ (Dupont et al, 2011; Low et al, 2014) provided further insights into how gene regulation occurs in response to biophysical cues.…”

“…The fate of NSCs is influenced by several soluble factors (SFs; top left), as widely described in the literature (Rivera et al, 2010), but is also modulated by several biophysical cues (top right) such as stiffness (Keung et al, 2011, 2012) and the combination of strain and insoluble factors like extracellular matrix (ECM) proteins (Arulmoli et al, 2015). Maturation of OLs is also influenced by SFs (Baumann and Pham-Dinh, 2001; top left), ECM composition (Buttery and ffrench-Constant, 1999; Colognato et al, 2004; bottom left) and biophysical elements, like stiffness (Kippert et al, 2009; Jagielska et al, 2012; Lourenço et al, 2016; top right), spatial constraints and cell density (Rosenberg et al, 2008; Hernandez et al, 2016) and topography (Lee et al, 2012; Bechler et al, 2015; bottom right).…”