H4K20me3 methyltransferase SUV420H2 shapes the chromatin landscape of pluripotent embryonic stem cells
H4K20me3 methyltransferase SUV420H2 shapes the chromatin landscape of pluripotent embryonic stem cells
复制标题
DOI：
10.1242/dev.188516
复制
发表时间：
2020-12-01
期刊：
影响因子：
4.6
通讯作者：
Kidder, Benjamin L.
中科院分区：
文献类型：
--
作者：
Kurup, Jiji T.;Han, Zhijun;Kidder, Benjamin L.
异染色质是一种转录缓慢的密集染色质状态，是基因表达的关键调节因子。然而，目前还不清楚抑制性组蛋白修饰H4 K20 me 3或组蛋白甲基转移酶SUV 420 H2如何通过模式化表观遗传景观来调节胚胎干细胞（ES）的命运。在这里，我们报告了SUV 420 H2的耗尽导致H4 K20 me 3全基因组几乎完全丧失，基因表达失调和ES细胞分化延迟。SUV 420 H2结合区域富含重复DNA元件，其在SUV 420 H2敲除ES细胞中被去抑制。此外，H4 K20 me 3标记的异染色质的SUV 420 H2调节控制染色质结构，包括多能ES细胞中的精细尺度染色质相互作用。我们的研究结果表明，SUV 420 H2在稳定ES细胞的三维染色质景观中起着至关重要的作用，因为SUV 420 H2的丢失导致A/B区室转换，扰乱染色质绝缘，并改变了臂间异染色质和周围区域的染色质相互作用，表明局部解凝聚。此外，SUV 420 H2的消耗导致H4 K20 me 3和基因调控区之间的相互作用受损。总之，这些发现描述了SUV 420 H2在调节ES细胞染色质景观中的新作用。
Heterochromatin, a densely packed chromatin state that is transcriptionally slent, is a critical regulator of gene expression. However, it is unclear how the repressive histone modification H4K20me3 or the histone methyltransferase SUV420H2 regulates embryonic stem (ES) cell fate by patterning the epigenetic landscape. Here, we report that depletion of SUV420H2 leads to a near-complete loss of H4K20me3 genome wide, dysregulated gene expression and delayed ES cell differentiation. SUV420H2-bound regions are enriched with repetitive DNA elements, which are de-repressed in SUV420H2 knockout ES cells. Moreover, SUV420H2 regulation of H4K20me3-marked heterochromatin controls chromatin architecture, induding finescale chromatin interactions in pluripotent ES cells. Our results indicate that SUV420H2 plays a crucial role in stabilizing the three-dimensional chromatin landscape of ES cells, as loss of SUV420H2 resulted in A/B compartment switching, perturbed chromatin insulation, and altered chromatin interactions of pericentric heterochromatin and surrounding regions, indicative of localized decondensation. In addition, depletion of SUV420H2 resulted in compromised interactions between H4K20me3 and gene-regulatory regions. Together, these findings describe a new role for SUV420H2 in regulating the chromatin landscape of ES cells.