NANOG prion-like assembly mediates DNA bridging to facilitate chromatin reorganization and activation of pluripotency.
NANOG prion-like assembly mediates DNA bridging to facilitate chromatin reorganization and activation of pluripotency.
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Nanog Prion样装配介导DNA桥接，以促进染色质重组和多能的激活。
DOI：
10.1038/s41556-022-00896-x
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发表时间：
2022-05
影响因子：
21.3
通讯作者：
中科院分区：
文献类型：
--
作者：
人类NANOG表达将干细胞重置为基态多能性。在这里，我们确定了人类NANOG的独特功能，涉及其作为主转录因子的剂量敏感功能。NANOG在很大程度上是无序的，具有C-末端朊病毒样结构域，其相变为凝胶样缩合物。全长NANOG在低纳摩尔浓度下容易形成高阶寡聚体，其数量级低于典型的淀粉样蛋白。使用单分子Förster共振能量转移和荧光互相关技术，我们表明，NANOG寡聚化是必不可少的体外桥接DNA元素。使用染色质免疫沉淀测序和Hi-C 3.0在细胞中，我们验证了NANOG朊病毒样结构域组装是必不可少的特异性DNA识别和远距离染色质相互作用。我们的研究结果为NANOG在塑造多能基因组中不可或缺的作用提供了物理基础。NANOG形成朊病毒样组装体的独特能力可以提供一种合作和协调的DNA桥接机制，这对于染色质重组和基态多能性的剂量敏感性激活至关重要。Choi等人报道，人NANOG蛋白在极低浓度下形成凝胶样缩合物，这促进了多能性维持所必需的染色质相互作用。
Human NANOG expression resets stem cells to ground-state pluripotency. Here we identify the unique features of human NANOG that relate to its dose-sensitive function as a master transcription factor. NANOG is largely disordered, with a C-terminal prion-like domain that phase-transitions to gel-like condensates. Full-length NANOG readily forms higher-order oligomers at low nanomolar concentrations, orders of magnitude lower than typical amyloids. Using single-molecule Förster resonance energy transfer and fluorescence cross-correlation techniques, we show that NANOG oligomerization is essential for bridging DNA elements in vitro. Using chromatin immunoprecipitation sequencing and Hi-C 3.0 in cells, we validate that NANOG prion-like domain assembly is essential for specific DNA recognition and distant chromatin interactions. Our results provide a physical basis for the indispensable role of NANOG in shaping the pluripotent genome. NANOG’s unique ability to form prion-like assemblies could provide a cooperative and concerted DNA bridging mechanism that is essential for chromatin reorganization and dose-sensitive activation of ground-state pluripotency. Choi et al. report that human NANOG proteins form gel-like condensates at extremely low concentrations, which facilitate the chromatin interaction that is essential for pluripotency maintenance.
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影响因子：
64.8
作者：
Dixon JR;Jung I;Selvaraj S;Shen Y;Antosiewicz-Bourget JE;Lee AY;Ye Z;Kim A;Rajagopal N;Xie W;Diao Y;Liang J;Zhao H;Lobanenkov VV;Ecker JR;Thomson JA;Ren B
通讯作者：
Ren B
影响因子：
5.2
作者：
Chang, David F.;Tsai, Steven C.;Lutzko, Carolyn
通讯作者：
Lutzko, Carolyn
影响因子：
64.5
作者：
Boija A;Klein IA;Sabari BR;Dall'Agnese A;Coffey EL;Zamudio AV;Li CH;Shrinivas K;Manteiga JC;Hannett NM;Abraham BJ;Afeyan LK;Guo YE;Rimel JK;Fant CB;Schuijers J;Lee TI;Taatjes DJ;Young RA
通讯作者：
Young RA
影响因子：
3.4
作者：
Chen, Y;Müller, JD;Gratton, E
通讯作者：
Gratton, E
影响因子：
4.8
作者：
Choi, Hee Jung;Kim, Iktae;Han, Jae Yong
通讯作者：
Han, Jae Yong