Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL 60637, USA.
Cell. 2012 Jun 22;149(7):1474-87. doi: 10.1016/j.cell.2012.04.035.
A large fraction of the mammalian genome is organized into inactive chromosomal domains along the nuclear lamina. The mechanism by which these lamina associated domains (LADs) are established remains to be elucidated. Using genomic repositioning assays, we show that LADs, spanning the developmentally regulated IgH and Cyp3a loci contain discrete DNA regions that associate chromatin with the nuclear lamina and repress gene activity in fibroblasts. Lamina interaction is established during mitosis and likely involves the localized recruitment of Lamin B during late anaphase. Fine-scale mapping of LADs reveals numerous lamina-associating sequences (LASs), which are enriched for a GAGA motif. This repeated motif directs lamina association and is bound by the transcriptional repressor cKrox, in a complex with HDAC3 and Lap2β. Knockdown of cKrox or HDAC3 results in dissociation of LASs/LADs from the nuclear lamina. These results reveal a mechanism that couples nuclear compartmentalization of chromatin domains with the control of gene activity.
哺乳动物基因组的很大一部分沿着核层粘连蛋白组织成非活性染色体结构域。这些核层粘连蛋白相关结构域（LAD）形成的机制仍有待阐明。通过基因组重定位分析，我们发现跨越发育调节的 IgH 和 Cyp3a 基因座的 LAD 包含与核层粘连蛋白相关并在成纤维细胞中抑制基因活性的离散 DNA 区域。层粘连蛋白相互作用是在有丝分裂期间建立的，可能涉及局部募集有丝分裂后期晚期的 lamin B。LAD 的精细图谱揭示了许多与层粘连蛋白相关的序列（LASs），这些序列富含 GAGA 基序。该重复基序指导层粘连蛋白的结合，并与转录抑制因子 cKrox 结合，形成与 HDAC3 和 Lap2β 的复合物。cKrox 或 HDAC3 的敲低导致 LASs/LAD 从核层粘连蛋白上解离。这些结果揭示了一种将染色质结构域的核区室化与基因活性控制相耦合的机制。
