50 years ago, Vincent Allfrey and colleagues discovered that lymphocyte activation triggers massive acetylation of chromatin. However, the molecular mechanisms driving epigenetic accessibility are still unknown. We here show that stimulated lymphocytes decondense chromatin by three differentially regulated steps. First, chromatin is repositioned away from the nuclear periphery in response to global acetylation. Second, histone nanodomain clusters decompact into mononucleosome fibers through a mechanism that requires Myc and continual energy input. Single-molecule imaging shows that this step lowers transcription factor residence time and non-specific collisions during sampling for DNA targets. Third, chromatin interactions shift from long range to predominantly short range, and CTCF-mediated loops and contact domains double in numbers. This architectural change facilitates cognate promoter-enhancer contacts and also requires Myc and continual ATP production. Our results thus define the nature and transcriptional impact of chromatin decondensation and reveal an unexpected role for Myc in the establishment of nuclear topology in mammalian cells.

50年前，文森特·阿弗雷（Vincent Allfrey）及其同事发现，淋巴细胞的活化会触发染色质的大量乙酰化。但是，驱动表观遗传可及性的分子机制仍是未知的。我们在这里显示受刺激的淋巴细胞通过三个差异调节的步骤使染色质浓缩。首先，响应于整体乙酰化，染色质被重新定位在远离核外围的位置。其次，组蛋白纳米域簇通过需要Myc和连续能量输入的机制分解为单核小体纤维。单分子成像显示，此步骤降低了DNA靶标采样期间的转录因子停留时间和非特异性碰撞。第三，染色质相互作用从长距离转变为短距离，并且CTCF介导的环和接触域的数量增加了一倍。这种结构上的变化促进了同源启动子-增强子的接触，并且还需要Myc和连续的ATP产生。因此，我们的结果定义了染色质缩聚的性质和转录影响，并揭示了Myc在哺乳动物细胞核拓扑学建立中的意外作用。