Department of Embryology, Carnegie Institution for Science, Baltimore, MD 21218, USA.
Department of Embryology, Carnegie Institution for Science, Baltimore, MD 21218, USA.
Mol Cell. 2018 Sep 6;71(5):802-815.e7. doi: 10.1016/j.molcel.2018.05.017. Epub 2018 Jun 28.
Lamins are structural components of the nuclear lamina (NL) that regulate genome organization and gene expression, but the mechanism remains unclear. Using Hi-C, we show that lamins maintain proper interactions among the topologically associated chromatin domains (TADs) but not their overall architecture. Combining Hi-C with fluorescence in situ hybridization (FISH) and analyses of lamina-associated domains (LADs), we reveal that lamin loss causes expansion or detachment of specific LADs in mouse ESCs. The detached LADs disrupt 3D interactions of both LADs and interior chromatin. 4C and epigenome analyses further demonstrate that lamins maintain the active and repressive chromatin domains among different TADs. By combining these studies with transcriptome analyses, we found a significant correlation between transcription changes and the interaction changes of active and inactive chromatin domains These findings provide a foundation to further study how the nuclear periphery impacts genome organization and transcription in development and NL-associated diseases.
核纤层蛋白是核纤层（NL）的结构组成部分，调节基因组组织和基因表达，但具体机制尚不清楚。我们使用 Hi-C 技术表明，核纤层蛋白维持拓扑相关染色质域（TAD）之间的适当相互作用，但不影响其整体结构。结合 Hi-C 与荧光原位杂交（FISH）以及核纤层相关结构域（LAD）的分析，我们揭示了核纤层缺失导致小鼠 ESC 中特定 LAD 的扩张或脱离。脱离的 LAD 破坏了 LAD 和内部染色质之间的三维相互作用。4C 和表观基因组分析进一步表明，核纤层蛋白维持不同 TAD 之间的活性和抑制性染色质域。通过将这些研究与转录组分析相结合，我们发现转录变化与活性和非活性染色质域的相互作用变化之间存在显著相关性。这些发现为进一步研究核周如何在发育和 NL 相关疾病中影响基因组组织和转录提供了基础。
