Departments of Medicine and Cell and Developmental Biology, Penn CVI, Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Smilow TRC, 3400 Civic Center Blvd, Philadelphia, PA, 19104, USA.
University of California, San Francisco, CA, 94117, USA.
Genome Biol. 2023 Jan 23;24(1):16. doi: 10.1186/s13059-023-02849-5.
Association of chromatin with lamin proteins at the nuclear periphery has emerged as a potential mechanism to coordinate cell type-specific gene expression and maintain cellular identity via gene silencing. Unlike many histone modifications and chromatin-associated proteins, lamina-associated domains (LADs) are mapped genome-wide in relatively few genetically normal human cell types, which limits our understanding of the role peripheral chromatin plays in development and disease.
To address this gap, we map LAMIN B1 occupancy across twelve human cell types encompassing pluripotent stem cells, intermediate progenitors, and differentiated cells from all three germ layers. Integrative analyses of this atlas with gene expression and repressive histone modification maps reveal that lamina-associated chromatin in all twelve cell types is organized into at least two subtypes defined by differences in LAMIN B1 occupancy, gene expression, chromatin accessibility, transposable elements, replication timing, and radial positioning. Imaging of fluorescently labeled DNA in single cells validates these subtypes and shows radial positioning of LADs with higher LAMIN B1 occupancy and heterochromatic histone modifications primarily embedded within the lamina. In contrast, the second subtype of lamina-associated chromatin is relatively gene dense, accessible, dynamic across development, and positioned adjacent to the lamina. Most genes gain or lose LAMIN B1 occupancy consistent with cell types along developmental trajectories; however, we also identify examples where the enhancer, but not the gene body and promoter, changes LAD state.
Altogether, this atlas represents the largest resource to date for peripheral chromatin organization studies and reveals an intermediate chromatin subtype.
核周层粘连蛋白与染色质的关联已成为一种潜在的机制，可以通过基因沉默来协调细胞类型特异性基因表达和维持细胞身份。与许多组蛋白修饰和染色质相关蛋白不同，板层相关结构域（LAD）在相对较少的遗传正常人类细胞类型中进行全基因组映射，这限制了我们对周边染色质在发育和疾病中作用的理解。
为了解决这一差距，我们在涵盖多能干细胞、中间祖细胞和来自三个胚层的分化细胞的 12 个人类细胞类型中绘制了 LAMIN B1 占有率图谱。对该图谱与基因表达和抑制性组蛋白修饰图谱的综合分析表明，所有 12 种细胞类型中的板层相关染色质都至少分为两种亚型，这两种亚型的区别在于 LAMIN B1 占有率、基因表达、染色质可及性、转座元件、复制定时和放射状定位的差异。对单个细胞中荧光标记 DNA 的成像验证了这些亚型，并显示出具有较高 LAMIN B1 占有率和异染色质组蛋白修饰的 LAD 的放射状定位主要嵌入在板层内。相比之下，第二种板层相关染色质亚型相对基因密度较高，在发育过程中具有可及性和动态性，并且定位在板层附近。大多数基因获得或失去与发育轨迹中的细胞类型一致的 LAMIN B1 占有率；然而，我们也发现了一些例子，其中增强子而不是基因体和启动子改变了 LAD 状态。
总的来说，这个图谱代表了迄今为止用于周边染色质组织研究的最大资源，并揭示了一种中间染色质亚型。
