染色质和细胞骨架束缚决定早老蛋白表达细胞的核形态
Chromatin and cytoskeletal tethering determine nuclear morphology in progerin expressing cells
摘要：
真核细胞的核形态是由构成核骨架的纤层、核内染色质以及与细胞骨架的偶联之间的相互作用决定的。核改变通常与病理状况相关，如在Hutchinson-Gilford早衰综合征（HGPS）中，其中核纤层蛋白A基因中的突变产生被称为早老蛋白的蛋白质的改变形式和异常的核形状。在这里，我们介绍了一种诱导型细胞模型的HGPS在HeLa细胞中，早老蛋白的表达增加导致改变的核纤层蛋白壳与细胞骨架/染色质系链以及与Polycomb组（PcG）蛋白的耦合。此外，我们的实验表明，早老蛋白的表达导致增强核形状的波动，响应于细胞骨架活性。为了解释实验结果，我们引入了一个计算模型的细胞核，其中明确包括染色质纤维，核壳和耦合与细胞骨架。该模型使我们能够调查的几何组织的染色质-核纤层蛋白系链影响核形态和形状波动。总之，我们的研究结果强调了核纤层染色质和核纤层细胞骨架的改变在决定核形态和影响细胞功能和基因调控中所起的关键作用。
英文摘要：
The nuclear morphology of eukaryotic cells is determined by the interplay between the lamina forming the nuclear skeleton, the chromatin inside the nucleus and the coupling with the cytoskeleton. Nuclear alterations are often associated with pathological conditions as in the Hutchinson-Gilford progeria syndrome (HGPS) where a mutation in the lamin A gene yields an altered form of the protein, named progerin, and an aberrant nuclear shape. Here, we introduce an inducible cellular model of HGPS in HeLa cells where increased progerin expression leads to alterations in the coupling of the lamin shell with cytoskeletal/chromatin tethers as well as with Polycomb-group (PcG) proteins. Furthermore, our experiments show that progerin expression leads to enhanced nuclear shape fluctuations in response to cytoskeletal activity. To interpret the experimental results, we introduce a computational model of the cell nucleus that includes explicitly chromatin fibers, the nuclear shell and the coupling with the cytoskeleton. The model allows us to investigate how the geometrical organization of chromatin-lamin tether affects nuclear morphology and shape fluctuations. In sum, our findings highlight the crucial role played by lamin-chromatin and lamin-cytoskeletal alterations in determining nuclear shape morphology and in affecting cellular functions and gene regulation.
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