LBR and Lamin A/C Sequentially Tether Peripheral Heterochromatin and Inversely Regulate Differentiation
LBR and Lamin A/C Sequentially Tether Peripheral Heterochromatin and Inversely Regulate Differentiation
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DOI：
10.1016/j.cell.2013.01.009
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发表时间：
2013-01-31
期刊：
影响因子：
64.5
通讯作者：
Joffe, Boris
中科院分区：
文献类型：
--
作者：
Solovei, Irina;Wang, Audrey S.;Joffe, Boris
真核细胞在核周围有一层异染色质。为了研究调节染色质分布的机制，我们分析了不同组织和物种中的异染色质组织，包括编码核膜（NE）蛋白的核纤层蛋白B受体（Lbr）和核纤层蛋白A（Lmna）基因突变的小鼠。我们确定了LBR和核纤层蛋白A/C依赖的机制拴系异染色质的NE。在细胞分化和发育过程中依次使用两个系链：首先是LBR依赖性系链，然后是层粘连蛋白A/C依赖性系链。LBR和核纤层蛋白A/C的缺失导致外周异染色质的丢失和异染色质定位于核内部的倒置结构。成肌细胞转录组分析表明，LBR或层粘连蛋白A依赖的异染色质系链的选择性破坏对肌肉基因表达有相反的影响，分别增加或减少。这些结果表明NE组成的变化如何有助于调节异染色质定位，基因表达和发育过程中的细胞分化。
Eukaryotic cells have a layer of heterochromatin at the nuclear periphery. To investigate mechanisms regulating chromatin distribution, we analyzed heterochromatin organization in different tissues and species, including mice with mutations in the lamin B receptor (Lbr) and lamin A (Lmna) genes that encode nuclear envelope (NE) proteins. We identified LBR- and lamin-A/C-dependent mechanisms tethering heterochromatin to the NE. The two tethers are sequentially used during cellular differentiation and development: first the LBR -and then the lamin-A/C-dependent tether. The absence of both LBR and lamin A/C leads to loss of peripheral heterochromatin and an inverted architecture with heterochromatin localizing to the nuclear interior. Myoblast transcriptome analyses indicated that selective disruption of the LBR- or lamin-A-dependent heterochromatin tethers have opposite effects on muscle gene expression, either increasing or decreasing, respectively. These results show how changes in NE composition contribute to regulating heterochromatin positioning, gene expression, and cellular differentiation during development.