Mammalian circadian oscillators are built on a feedback loop in which the activity of the transcription factor CLOCK–BMAL1 is repressed by the PER–CRY complex. Here, we show that murine Per^−/− fibroblasts display aberrant nucleosome occupancy around transcription start sites (TSSs) and at promoter-proximal and distal CTCF sites due to impaired histone H2A.Z deposition. Knocking out H2A.Z mimicked the Per null chromatin state and disrupted cellular rhythms. We found that endogenous mPER2 complexes retained CTCF as well as the specific H2A.Z-deposition chaperone YL1—a component of the ATP-dependent remodeler SRCAP and p400–TIP60 complex. While depleting YL1 or mutating chaperone-binding sites on H2A.Z lengthened the circadian period, H2A.Z deletion abrogated BMAL1 chromatin recruitment and promoted its proteasomal degradation. We propose that a PER2-mediated H2A.Z deposition pathway (1) compacts CLOCK–BMAL1 binding sites to establish negative feedback, (2) organizes circadian chromatin landscapes using CTCF and (3) bookmarks genomic loci for BMAL1 binding to impinge on the positive arm of the subsequent cycle.

哺乳动物昼夜节律振荡器建立在反馈回路上，其中转录因子 CLOCK-BMAL1 的活性被 PER-CRY 复合物抑制。在这里，我们表明，由于组蛋白 H2A.Z 沉积受损，小鼠Per ^{- / -成纤维细胞在转录起始位点 (TSS) 周围以及启动子近端和远端 CTCF 位点处显示出异常的核小体占据。}淘汰 H2A.Z 模仿了Per染色质无效状态和细胞节律紊乱。我们发现内源性 mPER2 复合物保留了 CTCF 以及特定的 H2A.Z 沉积伴侣 YL1——ATP 依赖性重塑物 SRCAP 和 p400-TIP60 复合物的一个组成部分。虽然耗尽 YL1 或突变 H2A.Z 上的伴侣结合位点延长了昼夜节律，但 H2A.Z 缺失消除了 BMAL1 染色质的募集并促进了其蛋白酶体降解。我们建议 PER2 介导的 H2A.Z 沉积途径 (1) 压缩 CLOCK-BMAL1 结合位点以建立​​负反馈，(2) 使用 CTCF 组织昼夜染色质景观和 (3) 标记基因组位点用于 BMAL1 结合以影响正反馈下一个周期的手臂。