Reversing chromatin dynamics for development Compacted chromatin regions, marked by trimethylation of histone H3 at position lysine 9 (H3K9me3), occur at highly repeated DNA sequences, helping to suppress recombination and gene expression. Because pluripotent cells contain low levels of H3K9me3 heterochromatin relative to differentiated cells, it has been thought that an increase in such heterochromatin helps to define cell differentiation. Nicetto et al. used two independent methods to examine compacted heterochromatic domains and found that H3K9me3 compaction increased at protein-coding genes during early mouse organogenesis. During differentiation, these domains open up to allow cell-specific expression. Loss of heterochromatin by genetic inactivation of the H3K9me3 methyltransferases caused ectopic expression of cell-inappropriate genes and tissue pathology. Science, this issue p. 294 H3K9me3-marked heterochromatin is deployed early in development but removed later for cell type–specific gene expression. Gene silencing by chromatin compaction is integral to establishing and maintaining cell fates. Trimethylated histone 3 lysine 9 (H3K9me3)–marked heterochromatin is reduced in embryonic stem cells compared to differentiated cells. However, the establishment and dynamics of closed regions of chromatin at protein-coding genes, in embryologic development, remain elusive. We developed an antibody-independent method to isolate and map compacted heterochromatin from low–cell number samples. We discovered high levels of compacted heterochromatin, H3K9me3-decorated, at protein-coding genes in early, uncommitted cells at the germ-layer stage, undergoing profound rearrangements and reduction upon differentiation, concomitant with cell type–specific gene expression. Perturbation of the three H3K9me3-related methyltransferases revealed a pivotal role for H3K9me3 heterochromatin during lineage commitment at the onset of organogenesis and for lineage fidelity maintenance.

中文翻译：

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蛋白质编码基因的 H3K9me3 异染色质丢失使发育谱系规范成为可能


逆转染色质动力学以促进发育紧凑的染色质区域以组蛋白 H3 在赖氨酸 9 (H3K9me3) 处的三甲基化为标志，出现在高度重复的 DNA 序列中，有助于抑制重组和基因表达。由于多能细胞相对于分化细胞含有较低水平的 H3K9me3 异染色质，因此人们认为这种异染色质的增加有助于定义细胞分化。尼塞托等人。使用两种独立的方法来检查压缩的异染色质结构域，发现在早期小鼠器官形成过程中，蛋白质编码基因的 H3K9me3 压缩增加。在分化过程中，这些结构域开放以允许细胞特异性表达。 H3K9me3 甲基转移酶基因失活导致异染色质丢失，导致细胞不适当基因和组织病理学的异位表达。科学，本期第 14 页。 294 H3K9me3 标记的异染色质在发育早期部署，但后来为了细胞类型特异性基因表达而被移除。通过染色质压缩实现的基因沉默对于建立和维持细胞命运至关重要。与分化细胞相比，胚胎干细胞中三甲基化组蛋白 3 赖氨酸 9 (H3K9me3) 标记的异染色质减少。然而，在胚胎发育过程中，蛋白质编码基因染色质封闭区域的建立和动态仍然难以捉摸。我们开发了一种不依赖于抗体的方法，从低细胞数样品中分离和绘制压缩异染色质图谱。我们在胚层阶段的早期未定型细胞的蛋白质编码基因中发现了高水平的压缩异染色质（H3K9me3 修饰），在分化时经历了深刻的重排和减少，并伴随着细胞类型特异性基因表达。 三种 H3K9me3 相关甲基转移酶的扰动揭示了 H3K9me3 异染色质在器官发生开始时的谱系定型和谱系保真度维持过程中的关键作用。