CAS Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou 511436, China; University of Chinese Academy of Sciences, Beijing 100049, China.
CAS Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou 511436, China.
Cell Stem Cell. 2017 Dec 7;21(6):819-833.e6. doi: 10.1016/j.stem.2017.10.012.
Cell-fate decisions remain poorly understood at the chromatin level. Here, we map chromatin remodeling dynamics during induction of pluripotent stem cells. ATAC-seq profiling of MEFs expressing Oct4-Sox2-Klf4 (OSK) reveals dynamic changes in chromatin states shifting from open to closed (OC) and closed to open (CO), with an initial burst of OC and an ending surge of CO. The OC loci are largely composed of genes associated with a somatic fate, while the CO loci are associated with pluripotency. Factors/conditions known to impede reprogramming prevent OSK-driven OC and skew OC-CO dynamics. While the CO loci are enriched for OSK motifs, the OC loci are not, suggesting alternative mechanisms for chromatin closing. Sap30, a Sin3A corepressor complex component, is required for the OC shift and facilitates reduced H3K27ac deposition at OC loci. These results reveal a chromatin accessibility logic during reprogramming that may apply to other cell-fate decisions.
细胞命运决定在染色质水平上仍未得到很好的理解。在这里，我们绘制了诱导多能干细胞过程中染色质重塑动力学图谱。表达 Oct4-Sox2-Klf4（OSK）的 MEFs 的 ATAC-seq 分析揭示了染色质状态的动态变化，从开放到关闭（OC）和从关闭到开放（CO），最初出现 OC 爆发，最后出现 CO 激增。OC 位置主要由与体细胞命运相关的基因组成，而 CO 位置与多能性相关。已知会阻碍重编程的因素/条件会阻止 OSK 驱动的 OC 并使 OC-CO 动力学发生偏差。虽然 CO 位置富含 OSK 基序，但 OC 位置则没有，这表明染色质关闭有替代机制。Sap30 是 Sin3A 核心抑制复合物的组成部分，是 OC 转变所必需的，可促进 OC 位置处 H3K27ac 沉积减少。这些结果揭示了重编程过程中的染色质可及性逻辑，该逻辑可能适用于其他细胞命运决定。
