Nuclear Stiffness is Differentially Regulated by Lamin Isoforms

Presenter: Andy Li

Faculty Sponsor: Andrew Stephens

School: UMass Amherst

Research Area: Biology

Session: Poster Session 6, 4:15 PM - 5:00 PM, Auditorium, A25

ABSTRACT

The mechanical properties of the nucleus are critical for maintaining nuclear integrity and function, and disruptions in these mechanics are linked to dysfunction. We previously showed that chromatin dominates short-extension mechanics, while lamins provide long-extension strain stiffening. To distinguish the roles of lamin isoforms, micromanipulation nucleus force measurements were performed on isolated nuclei from mouse embryonic fibroblast lines depleted of lamin B (LMNB1-/-), lamin A (LA KD), and lamin A and C (LMNA-/-).  Loss of lamin B nuclei exhibit reduced short-extension stiffness while maintaining long-extension mechanics, due to loss of facultative heterochromatin. Loss of lamin A and C did not alter short-extension nuclear stiffness. Nuclei depleted of lamin A display weaker stiffness in long extensions, whereas loss of both lamin A and C nuclei show a dramatic loss of strain stiffening in the long regime. These results support a model in which lamin B has no direct nuclear stiffness role and that lamin A and C are equally responsible for long-regime nuclear strain stiffening. It is hypothesized that lamin B influences nuclear stiffness indirectly through effects on chromatin organization and heterochromatin-mediated resistance at small deformations, rather than by directly bearing tensile load at large deformations (Schreiner et al., 2015; Stephens et al., 2019; Manning et al., 2025). This work illuminates the distinct mechanical roles for lamin isoforms, and establishes a foundation for understanding how nuclear structure is determined in health and disease.

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