DAXX safeguards heterochromatin formation in embryonic stem cells
DAXX safeguards heterochromatin formation in embryonic stem cells
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DOI：
10.1101/2021.04.28.441827
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发表时间：
2021-04
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影响因子：
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通讯作者：
Antoine Canat;Adeline Veillet;Renaud Batrin;Clara Dubourg;Robert S. Illingworth;E. Fabre;Pierre Therizols-Pie
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作者：
Antoine Canat;Adeline Veillet;Renaud Batrin;Clara Dubourg;Robert S. Illingworth;E. Fabre;Pierre Therizols-Pie
基因组包含大部分折叠成组成型异染色质的重复序列，以保护基因组完整性和细胞身份。异染色质的重新形成是胚胎干细胞（ESCs）在着床前发育过程中保持多能性和自我更新能力的基础状态的重要步骤。然而，负责组成性异染色质重塑的分子机制在很大程度上是未知的。在这里，我们发现DAXX，一种H3.3分子伴侣，是胚胎干细胞维持多能性基态所必需的。DAXX聚集在着丝粒周围区域，并募集PML和SETDB 1，从而促进异染色质形成。在没有DAXX或PML的情况下，臂间和外周异染色质的3D结构和物理性质被破坏，导致主要卫星DNA、转座因子和与核纤层相关的基因的去抑制。使用表观基因组编辑工具，我们观察到H3.3，特别是H3.3K9修饰，直接有助于维持近着丝粒染色质构象。总而言之，我们的数据表明DAXX对于异染色质区室的维持和3D组织至关重要，并保护ESC的活力。
Genomes comprise a large fraction of repetitive sequences folded into constitutive heterochromatin to protect genome integrity and cell identity. De novo formation of heterochromatin during preimplantation development is an essential step for preserving the ground-state of pluripotency and the self-renewal capacity of embryonic stem cells (ESCs). Yet, the molecular mechanisms responsible for the remodeling of constitutive heterochromatin are largely unknown. Here, we find that DAXX, an H3.3 chaperone, is essential for ESCs maintenance in the ground-state of pluripotency. DAXX accumulates at pericentromeric regions, and recruits PML and SETDB1, thereby promoting heterochromatin formation. In absence of DAXX or PML, the 3D-architecture and physical properties of pericentric and peripheral heterochromatin are disrupted, resulting in derepression of major satellite DNA, transposable elements and genes associated with the nuclear lamina. Using epigenome editing tools, we observe that H3.3, and specifically H3.3K9 modification, directly contribute to maintaining pericentromeric chromatin conformation. Altogether, our data reveal that DAXX is crucial for the maintenance and 3D-organization of the heterochromatin compartment and protects ESCs viability.