Epigenetic mechanisms enable cells to develop novel adaptive phenotypes without altering their genetic blueprint. Recent studies show histone modifications, such as heterochromatin-defining H3K9 methylation (H3K9me), can be redistributed to establish adaptive phenotypes. We developed a precision-engineered genetic approach to trigger heterochromatin misregulation on-demand in fission yeast. This enabled us to trace genome-scale RNA and H3K9me changes over time in long-term, continuous cultures. Adaptive H3K9me establishes over remarkably slow timescales relative to the initiating stress. We captured dynamic H3K9me redistribution events which depend on an RNA binding complex MTREC, ultimately leading to cells converging on an optimal adaptive solution. Upon stress removal, cells relax to new transcriptional and chromatin states, establishing memory that is tunable and primed for future adaptive epigenetic responses. Collectively, we identify the slow kinetics of epigenetic adaptation that allow cells to discover and heritably encode novel adaptive solutions, with implications for drug resistance and response to infection.

表观遗传机制使细胞能够在不改变其遗传蓝图的情况下发展出新的适应性表型。最近的研究表明，组蛋白修饰，例如异染色质定义的 H3K9 甲基化 (H3K9me)，可以重新分布以建立适应性表型。我们开发了一种精确设计的遗传方法，可以在裂殖酵母中按需触发异染色质失调。这使我们能够在长期、连续培养中追踪基因组规模的 RNA 和 H3K9me 随着时间的变化。相对于初始压力，自适应 H3K9me 的建立时间尺度非常慢。我们捕获了依赖于 RNA 结合复合物 MTREC 的动态 H3K9me 重新分布事件，最终导致细胞收敛于最佳自适应解决方案。压力消除后，细胞放松到新的转录和染色质状态，建立可调节的记忆，并为未来的适应性表观遗传反应做好准备。总的来说，我们确定了表观遗传适应的缓慢动力学，它使细胞能够发现并遗传编码新的适应性解决方案，这对耐药性和对感染的反应具有影响。