Abstract
The cause of nuclear shape abnormalities which are often seen in pre-neoplastic and malignant tissues is not clear. In this study we report that deformation of the nucleus can be induced by TGFβ1 stimulation in several cell lines including Huh7. In our results, the upregulated histone H3.3 expression downstream of SMAD signaling contributed to TGFβ1-induced nuclear deformation, a process of which requires incorporation of the nuclear envelope (NE) proteins lamin B1 and SUN1. During this process, the NE constitutively ruptured and reformed. Contrast to lamin B1 which was relatively stationary around the nucleus, the upregulated lamin A was highly mobile, clustering at the nuclear periphery and reintegrating into the nucleoplasm. The chromatin regions that lost NE coverage formed a supra-nucleosomal structure characterized by elevated histone H3K27me3 and histone H1, the formation of which depended on the presence of lamin A. These results provide evidence that shape of the nucleus can be modulated through TGFβ1-induced compositional changes in the chromatin and nuclear lamina.
Highlights
The cell nucleus is a double membrane-enclosed organelle
In addition to the dramatic phenotypic change, such as loss cell–cell adhesion and profound reorganization of the cytoskeleton (Additional file 1: Fig. S1A), we serendipitously discovered that the nuclear morphology of Huh7 hepatocellular carcinoma cells became abnormally shaped when treated with TGFβ1 (Fig. 1A), concomitant with increases in the expression of mesenchymal markers N-Cadherin and Vimentin (Fig. 1B)
Using elliptic Fourier analysis (EFA) to compute elliptic axial ratios (ARs) describing the nuclear shape [23], we identified a drastic increase in shape abnormalities in TGFβ1-treated nuclei (Fig. 1G, H)
Summary
The cell nucleus is a double membrane-enclosed organelle. Most nuclei appear spheroid or ellipsoid; the shape can vary from trilobed in human neutrophils to dumbbell-shaped in some white blood cells. Nuclear atypia which refers to abnormally shaped cell nuclei is a term used in cytopathology, and is considered a significant indicator of malignancy [1]. Changes in nuclear shape have been linked to chromatin reorganization and gene expression [5, 8]; the molecular signaling. High lamin A levels can physically stabilize the nucleus against stress and thereby protect the nuclear lamina and chromatin. It is suggested that the mechanical signals transmitted from the extracellular environment to the nucleus mediated by the cytoskeleton may fine tune the lamin A:B for cell-specific gene expression [10]. Abnormalities in the nuclear lamina are hallmarks of many human diseases [11]. Different types of lamina abnormality, such as herniations, honeycomb-like structures, and irregular staining, have been observed in
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