H3K9me3-heterochromatin loss at protein-coding genes enables developmental lineage specification
H3K9me3-heterochromatin loss at protein-coding genes enables developmental lineage specification
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DOI：
10.1126/science.aau0583
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发表时间：
2019-01-18
期刊：
影响因子：
56.9
通讯作者：
Zaret, Kenneth S.
中科院分区：
文献类型：
--
作者：
Nicetto, Dario;Donahue, Greg;Zaret, Kenneth S.
通过染色质压缩的基因沉默对于建立和维持细胞命运是不可或缺的。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，在胚胎发育中，蛋白质编码基因染色质封闭区域的建立和动态变化仍然是难以捉摸的。我们开发了一种不依赖抗体的方法，从低细胞数样品中分离和映射致密异染色质。我们发现高水平的压实异染色质，H3K9me3装饰，在蛋白质编码基因的早期，未定型细胞在胚层阶段，经历深刻的重排和减少分化后，伴随着细胞类型特异性基因表达。三个H3K9me3相关的甲基转移酶的扰动揭示了H3K9me3异染色质在器官发生的谱系承诺和谱系保真度维持过程中的关键作用。
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.