The nuclear envelope: LINCing tissue mechanics to genome regulation in cardiac and skeletal muscle

Abstract

<jats:p>Regulation of the genome is viewed through the prism of gene expression, DNA replication and DNA repair as controlled through transcription, chromatin compartmentalisation and recruitment of repair factors by enzymes such as DNA polymerases, ligases, acetylases, methylases and cyclin-dependent kinases. However, recent advances in the field of muscle cell physiology have also shown a compelling role for ‘outside-in’ biophysical control of genomic material through mechanotransduction. The crucial hub that transduces these biophysical signals is called the Linker of Nucleoskeleton and Cytoskeleton (LINC). This complex is embedded across the nuclear envelope, which separates the nucleus from the cytoplasm. How the LINC complex operates to mechanically regulate the many functions of DNA is becoming increasingly clear, and recent advances have provided exciting insight into how this occurs in cells from mechanically activated tissues such as skeletal and cardiac muscle. Nevertheless, there are still some notable shortcomings in our understanding of these processes and resolving these will likely help us understand how muscle diseases manifest at the level of the genome.</jats:p>

Mechanotransduction in Prokaryotes: A Possible Mechanism of Spaceflight Adaptation

“…Furthermore, the cytoskeleton and nucleoskeleton are physically connected through Linker of Nucleus and Cytoskeleton (LINC) protein complexes [ 16 ] ( Figure 1 ). Evidence is accumulating that LINC complexes allow for the rapid mechanotransduction of signals from the cytoplasmic membrane and cytoskeleton directly through the nuclear membrane to the nucleoskeleton, enabling rapid gene expression responses (reviewed in [ 17 ]). It is thought that the LINC complex is intimately involved in modulation of genome expression in response to mechanical stimuli through chromatin remodeling and recruitment of DNA and RNA polymerases, ligases, acetylases, methylases, and cyclin-dependent kinases, resulting in changes in gene expression at the transcriptional, translational, post-translational, and epigenetic levels [ 19 , 20 ].…”

“…It is thought that the LINC complex is intimately involved in modulation of genome expression in response to mechanical stimuli through chromatin remodeling and recruitment of DNA and RNA polymerases, ligases, acetylases, methylases, and cyclin-dependent kinases, resulting in changes in gene expression at the transcriptional, translational, post-translational, and epigenetic levels [ 19 , 20 ]. The details of the myriad of eukaryotic mechanotransduction systems, though not yet completely elucidated, are currently being actively investigated [ 17 ].…”

“…Colored shapes represent proteins in the transduction pathway; their specific identities and functions are elaborated in refs. [ 15 , 16 , 17 ]. See text for details.…”

Analysis of cardiomyocyte nuclei in human cardiomyopathy reveals orientation dependent defects in shape

“…Intranuclear mechanisms may also be important, since the nucleoskeleton and chromatin are both mechanically operative and may respond to external stimuli in ways which cause the mis-regulation of discreet regions of DNA with potential effects on transcription, DNA replication and DNA integrity (16,(22)(23)(24). Although human heart tissue in…”

Nucleus-Cytoskeleton Crosstalk During Mitotic Entry

“…Importantly, timely progression through these steps requires the activity of mitotic kinases such as CDK1 and PLK1 (Gavet and Pines, 2010b;Ramanathan et al, 2015;Gheghiani et al, 2017). Simultaneously, within the nucleus, a cascade of events regulated by the same mitotic kinases initiate chromosome condensation (Abe et al, 2011) and trigger disassembly of the nuclear pore complex (NPC;Linder et al, 2017) and nuclear lamina (NL; Heald and McKeon, 1990;Peter et al, 1990).…”