Stem Cell Epigenetics Laboratory, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, and Norwegian Center for Stem Cell Research, Blindern, 0317 Oslo, Norway;
Genome Res. 2013 Oct;23(10):1580-9. doi: 10.1101/gr.159400.113. Epub 2013 Jul 16.
The nuclear lamina is implicated in the organization of the eukaryotic nucleus. Association of nuclear lamins with the genome occurs through large chromatin domains including mostly, but not exclusively, repressed genes. How lamin interactions with regulatory elements modulate gene expression in different cellular contexts is unknown. We show here that in human adipose tissue stem cells, lamin A/C interacts with distinct spatially restricted subpromoter regions, both within and outside peripheral and intra-nuclear lamin-rich domains. These localized interactions are associated with distinct transcriptional outcomes in a manner dependent on local chromatin modifications. Down-regulation of lamin A/C leads to dissociation of lamin A/C from promoters and remodels repressive and permissive histone modifications by enhancing transcriptional permissiveness, but is not sufficient to elicit gene activation. Adipogenic differentiation resets a large number of lamin-genome associations globally and at subpromoter levels and redefines associated transcription outputs. We propose that lamin A/C acts as a modulator of local gene expression outcome through interaction with adjustable sites on promoters, and that these position-dependent transcriptional readouts may be reset upon differentiation.
核层与真核细胞核的组织有关。核纤层与基因组的结合发生在包括大多数（但并非完全）沉默基因的大染色质域中。核纤层与调节元件的相互作用如何在不同的细胞环境中调节基因表达尚不清楚。我们在这里显示，在人类脂肪组织干细胞中，核纤层蛋白 A/C 与内部和外部周边核纤层丰富区域内和之间的不同空间限制亚启动子区域相互作用。这些局部相互作用以依赖于局部染色质修饰的方式与不同的转录结果相关。核纤层蛋白 A/C 的下调导致核纤层蛋白 A/C 从启动子上解离，并通过增强转录的许可性重塑抑制性和许可性组蛋白修饰，但不足以引发基因激活。脂肪生成分化在全局和亚启动子水平上重置了大量核纤层-基因组的关联，并重新定义了相关的转录输出。我们提出，核纤层蛋白 A/C 通过与启动子上的可调位点相互作用，作为局部基因表达结果的调节剂，并且这些位置依赖性转录读出可以在分化时重置。
