Chromatin's physical properties shape the nucleus and its functions

Abstract

The cell nucleus encloses, organizes, and protects the genome. Chromatin maintains nuclear mechanical stability and shape in coordination with lamins and the cytoskeleton. Abnormal nuclear shape is a diagnostic marker for human diseases, and it can cause nuclear dysfunction. Chromatin mechanics underlies this link, as alterations to chromatin and its physical properties can disrupt or rescue nuclear shape. The cell can regulate nuclear shape through mechanotransduction pathways that sense and respond to extracellular cues, thus modulating chromatin compaction and rigidity. These findings reveal how chromatin's physical properties can regulate cellular function and drive abnormal nuclear morphology and dysfunction in disease.

Figure 1. Chromatin is a major contributor to nuclear mechanics and shape along with lamins and the cytoskeleton.

(A) The major protective mechanical components of the nucleus that aid nuclear shape stability are chromatin (blue), which is a stiff polymer gel, and lamins (green), which are an intermixed meshwork of easily bendable intermediate filaments of lamin A, B1, B2, and C. The cytoskeleton components actin (purple) and microtubules (orange) antagonize nuclear shape stability, although actin and vimentin (not shown) can also aid stability. (B) Top: Schematic showing differential force response regimes arising due to geometric considerations for lamins (a 2D meshwork) and chromatin (a 3D gel). For short, few-micron deformations (i.e., small strains), the chromatin gel acts as a spring that resists stretching, while lamins contribute little as they bend easily until they are aligned with the tension axis. Longer deformations, for which the lamins are aligned with the force, generate lamin-A-based strain stiffening. Chromatin continues to resist stretching of the nucleus at long deformations as a secondary component. Bottom: Abnormal nuclear shape and blebs are small deformations, occurring in the regime dominated by chromatin. During migration through pores, the nucleus extends many microns (>3 µm) into a deformation regime that necessitates and activates lamin A resistance to maintain shape stability. Failure to maintain shape stability in either condition can result in disruption of transcription through chromatin disorganization or blebs that inhibit it. Either shape disruption can result in nuclear ruptures that lead to DNA damage and loss of nuclear compartmentalization.