Ma Yiqin, Buttitta Laura
Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, 48109, USA.
Epigenetics Chromatin. 2017 Nov 10;10(1):53. doi: 10.1186/s13072-017-0159-8.
Genome organization changes during development as cells differentiate. Chromatin motion becomes increasingly constrained and heterochromatin clusters as cells become restricted in their developmental potential. These changes coincide with slowing of the cell cycle, which can also influence chromatin organization and dynamics. Terminal differentiation is often coupled with permanent exit from the cell cycle, and existing data suggest a close relationship between a repressive chromatin structure and silencing of the cell cycle in postmitotic cells. Heterochromatin clustering could also contribute to stable gene repression to maintain terminal differentiation or cell cycle exit, but whether clustering is initiated by differentiation, cell cycle changes, or both is unclear. Here we examine the relationship between chromatin organization, terminal differentiation and cell cycle exit.
We focused our studies on the Drosophila wing, where epithelial cells transition from active proliferation to a postmitotic state in a temporally controlled manner. We find there are two stages of G in this tissue, a flexible G period where cells can be induced to reenter the cell cycle under specific genetic manipulations and a state we call "robust," where cells become strongly refractory to cell cycle reentry. Compromising the flexible G by driving ectopic expression of cell cycle activators causes a global disruption of the clustering of heterochromatin-associated histone modifications such as H3K27 trimethylation and H3K9 trimethylation, as well as their associated repressors, Polycomb and heterochromatin protein 1 (HP1). However, this disruption is reversible. When cells enter a robust G state, even in the presence of ectopic cell cycle activity, clustering of heterochromatin-associated modifications is restored. If cell cycle exit is bypassed, cells in the wing continue to terminally differentiate, but heterochromatin clustering is severely disrupted. Heterochromatin-dependent gene silencing does not appear to be required for cell cycle exit, as compromising the H3K27 methyltransferase Enhancer of zeste, and/or HP1 cannot prevent the robust cell cycle exit, even in the face of normally oncogenic cell cycle activities.
Heterochromatin clustering during terminal differentiation is a consequence of cell cycle exit, rather than differentiation. Compromising heterochromatin-dependent gene silencing does not disrupt cell cycle exit.
随着细胞分化，基因组组织在发育过程中发生变化。随着细胞的发育潜能受到限制，染色质运动变得越来越受限，异染色质聚集。这些变化与细胞周期的减慢同时发生，细胞周期的减慢也会影响染色质的组织和动力学。终末分化通常与细胞周期的永久退出相关，现有数据表明有丝分裂后细胞中抑制性染色质结构与细胞周期沉默之间存在密切关系。异染色质聚集也可能有助于稳定的基因抑制，以维持终末分化或细胞周期退出，但聚集是由分化、细胞周期变化还是两者共同引发尚不清楚。在这里，我们研究染色质组织、终末分化和细胞周期退出之间的关系。
我们将研究重点放在果蝇翅膀上，其中上皮细胞以时间可控的方式从活跃增殖转变为有丝分裂后状态。我们发现在这个组织中有两个G期阶段，一个是灵活的G期，在此期间细胞可以在特定的基因操作下被诱导重新进入细胞周期，另一个是我们称为“稳健”的状态，在此状态下细胞对细胞周期重新进入变得强烈抵抗。通过驱动细胞周期激活剂的异位表达来破坏灵活的G期会导致异染色质相关组蛋白修饰（如H3K27三甲基化和H3K9三甲基化）及其相关抑制因子（多梳蛋白和异染色质蛋白1（HP1））聚集的全局破坏。然而，这种破坏是可逆的。当细胞进入稳健的G期状态时，即使存在异位细胞周期活性，异染色质相关修饰的聚集也会恢复。如果绕过细胞周期退出，翅膀中的细胞会继续终末分化，但异染色质聚集会严重破坏。异染色质依赖性基因沉默似乎不是细胞周期退出所必需的，因为破坏H3K27甲基转移酶zeste增强子和/或HP1并不能阻止稳健的细胞周期退出，即使面对通常致癌的细胞周期活性。
终末分化过程中的异染色质聚集是细胞周期退出的结果，而不是分化的结果。破坏异染色质依赖性基因沉默不会破坏细胞周期退出。
