A Mechano-Feedback Loop Orchestrated by SUN1/2 Governs Cellular Mechanoadaptation via Lamina-Associated Domain...

Area of Science:

• Cell Biology
• Mechanobiology
• Molecular Biology

Background:

• SUN1 and SUN2 are key components of the Linker of Nucleoskeleton and Cytoskeleton (LNCS) complex.
• The LNCS complex transmits extracellular mechanical forces to the nuclear lamina and chromatin.
• The role of SUN1/2 in peripheral chromatin regulation during mechanosensing and mechanoadaptation is not well understood.

Purpose of the Study:

• To investigate the role of SUN1/2 in regulating peripheral chromatin organization.
• To identify the mechano-feedback mechanisms involving SUN1/2 in myoblasts.
• To elucidate the functional consequences of SUN1/2 depletion on cell adhesion, mechanotransduction, and differentiation.

Main Methods:

• CRISPR/Cas9-mediated knockout of SUN1 or SUN2 in C2C12 myoblasts.
• Analysis of gene expression related to cell adhesion and mechanotransduction.
• Assessment of heterochromatin redistribution and lamina-associated domain (LAD) remodeling.
• Functional assays for myoblast differentiation and response to mechanical cues.
• Investigation of lamin A/C as a downstream effector.

Main Results:

• SUN1/2 depletion leads to down-regulation of cell adhesion and mechanotransduction genes.
• Loss of SUN1/2 causes heterochromatin redistribution from the nuclear periphery to the nucleoplasm and LAD remodeling.
• Lamin A/C acts as a downstream effector, modulating adhesion gene expression via LAD remodeling.
• Knockout of SUN1/2 or Lmna exacerbates differentiation defects and abolishes adaptive responses to mechanical stimuli.

Conclusions:

• A SUN1/2-dependent mechano-feedback loop coordinates LAD reorganization with the expression of upstream mechanotransduction genes.
• Nuclear mechanotransduction proteins modulate cellular mechanoadaptation through this feedback loop.
• This pathway is critical for myoblast differentiation and adaptive responses to mechanical cues.