Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, San Diego, CA 92037, USA.
Sci Adv. 2018 Aug 22;4(8):eaat6224. doi: 10.1126/sciadv.aat6224. eCollection 2018 Aug.
Heterochromatin formation during early embryogenesis is timed precisely, but how this process is regulated remains elusive. We report the discovery of a histone methyltransferase complex whose nuclear accumulation and activation establish the onset of heterochromatin formation in embryos. We find that the inception of heterochromatin generation coincides with the accumulation of the histone H3 lysine 9 (H3K9) methyltransferase MET-2 (SETDB) into nuclear hubs. The absence of MET-2 results in delayed and disturbed heterochromatin formation, whereas accelerated nuclear localization of the methyltransferase leads to precocious H3K9 methylation. We identify two factors that bind to and function with MET-2: LIN-65, which resembles activating transcription factor 7-interacting protein (ATF7IP) and localizes MET-2 into nuclear hubs, and ARLE-14, which is orthologous to adenosine 5'-diphosphate-ribosylation factor-like 14 effector protein (ARL14EP) and promotes stable association of MET-2 with chromatin. These data reveal that nuclear accumulation of MET-2 in conjunction with LIN-65 and ARLE-14 regulates timing of heterochromatin domains during embryogenesis.
早期胚胎发生过程中的异染色质形成时间精确，但这一过程如何被调控仍然难以捉摸。我们报告了一个组蛋白甲基转移酶复合物的发现，其核积累和激活确立了 胚胎中异染色质形成的开始。我们发现，异染色质生成的开始与组蛋白 H3 赖氨酸 9（H3K9）甲基转移酶 MET-2（SETDB）积累到核中心相吻合。MET-2 的缺失导致异染色质形成延迟和紊乱，而甲基转移酶的核定位加速则导致过早的 H3K9 甲基化。我们鉴定了两个与 MET-2 结合并发挥作用的因子：LIN-65，它类似于激活转录因子 7 相互作用蛋白（ATF7IP），并将 MET-2 定位到核中心；以及 ARLE-14，它与腺苷 5'-二磷酸-核糖基化因子样 14 效应蛋白（ARL14EP）同源，并促进 MET-2 与染色质的稳定结合。这些数据揭示了 MET-2 与 LIN-65 和 ARLE-14 的核积累共同调节胚胎发生过程中异染色质域的时间。
