InterLINCing Chromatin Organization and Mechanobiology in Laminopathies

Abstract

Purpose of review: In this review, we explore the chromatin-related consequences of laminopathy-linked mutations through the lens of mechanotransduction.

Recent findings: Multiple studies have highlighted the role of the nuclear lamina in maintaining the integrity of the nucleus. The lamina also has a critical role in 3D genome organization. Mutations in lamina proteins associated with various laminopathies result in the loss of organization of DNA at the nuclear periphery. However, it remains unclear if or how these two aspects of lamin function are connected. Recent data suggests that unlinking the cytoskeleton from the nuclear lamina may be beneficial to slow progress of deleterious phenotypes observed in laminopathies. In this review, we highlight emerging data that suggest interlinked chromatin- and mechanical biology-related pathways are interconnected in the pathogenesis of laminopathies.

Keywords: Epigenetics; Lamin; Laminopathy; Mechanobiology.

Fig. 1

Model: Mechanical force is critical for normal genome organization. Top left: Wild type cells exhibit normal force transduction to the nucleus via the LINC complex and have normal LADs at the nuclear periphery. Top right: Cells with perturbations of the nuclear lamina via mutations in LMNA feature compromised LADs and aberrant upregulation of non-lineage genes. Bottom right: Cells with perturbations to the LINC complex via SUN1 deletion may demonstrate compromised LAD organization, leading to aberrant gene expression and failure to properly respond to mechanical stimuli. Bottom left: Perturbation of the LINC complex in LMNA mutant conditions may preserve LAD organization and prevent abnormal gene expression, based on observations of Lmna mutant defects (partially) ameliorated with concomitant SUN1 loss. Figure created with BioRender.com