Pluripotency factors functionally premark cell-type-restricted enhancers in ES cells.
Pluripotency factors functionally premark cell-type-restricted enhancers in ES cells.
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DOI：
10.1038/s41586-018-0048-8
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发表时间：
2018-04
期刊：
影响因子：
64.8
通讯作者：
Rosenfeld MG
中科院分区：
文献类型：
--
作者：
Kim HS;Tan Y;Ma W;Merkurjev D;Destici E;Ma Q;Suter T;Ohgi K;Friedman M;Skowronska-Krawczyk D;Rosenfeld MG
虽然胚胎干细胞(ESC)表达的基因和谱系决定因子的增强子具有胚胎干细胞中传统的增强子激活标记的特征，但目前尚不清楚调控细胞类型受限转录单位的增强子是否也有一些目前被忽视的独特特征。在这里，我们报告了细胞类型受限的增强子，意外地被一个或两个ESC转录因子结合作为转录单位标记并激活，尽管在ESCs中没有表现出传统的增强子表观遗传学标记，从而揭示了细胞类型受限增强子的最初时间起源。这种前置标记对于分化细胞中未来的细胞类型限制性增强子活性是必需的，而ESCS签名的强度对于随后细胞类型限制性增强子激活的稳健性是重要的。这个模型已经在巨噬细胞限制性增强子和神经前体细胞限制性增强子中进行了实验验证，这些增强子使用ESCs来源的巨噬细胞或NPC，编辑后包含特定的ESC转录因子基序缺失。ESC转录因子决定了ESCS中增强子的DNA羟甲基化，这可能是随后在成熟巨噬细胞中激活增强子的潜在分子记忆。这些发现表明，大量的细胞类型受限的增强子基本上是由ESCs中一个定义的ESC转录因子的结合来分级和强制性地“标记”的，这决定了成熟细胞中增强子激活的稳健性。
While enhancers for embryonic stem cell (ESC)-expressed genes and lineage-determining factors are characterized by conventional marks of enhancer activation in ESCs, it remains unclear whether enhancers destined to regulate cell-type-restricted transcription units might also have some currently overlooked, distinct signatures in ESCs. Here, we report that cell-type-restricted enhancers, are unexpectedly premarked and activated as transcription units by the binding of a single, or two, ESC transcription factors, although not exhibiting traditional enhancer epigenetic marks in ESCs, thus uncovering the initial temporal origins of cell-type-restricted enhancers. This premarking is required for future cell-type-restricted enhancer activity in the differentiated cells, with the strength of the ESCs signature being functionally important for subsequent robustness of cell-type-restricted enhancer activation. This model has been experimentally validated in macrophage-restricted enhancers and neural precursor cells (NPCs)-restricted enhancers using ESCs-derived macrophages or NPCs, edited to contain specific ESC transcription factor motif deletions. The ESC transcription factor-determined DNA hydroxyl-methylation of the enhancers in ESCs may serve as a potential molecular memory for subsequent enhancer activation in the mature macrophage. These findings suggest that the massive repertoire of cell-type-restricted enhancers are essentially hierarchically and obligatorily “premarked” by binding of a defining ESC transcription factor in ESCs, dictating robustness of enhancer activation in mature cells.
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影响因子：
64.8
作者：
Heintzman, Nathaniel D.;Hon, Gary C.;Hawkins, R. David;Kheradpour, Pouya;Stark, Alexander;Harp, Lindsey F.;Ye, Zhen;Lee, Leonard K.;Stuart, Rhona K.;Ching, Christina W.;Ching, Keith A.;Antosiewicz-Bourget, Jessica E.;Liu, Hui;Zhang, Xinmin;Green, Roland D.;Lobanenkov, Victor V.;Stewart, Ron;Thomson, James A.;Crawford, Gregory E.;Kellis, Manolis;Ren, Bing
通讯作者：
Ren, Bing
影响因子：
64.5
作者：
Phillips-Cremins JE;Sauria ME;Sanyal A;Gerasimova TI;Lajoie BR;Bell JS;Ong CT;Hookway TA;Guo C;Sun Y;Bland MJ;Wagstaff W;Dalton S;McDevitt TC;Sen R;Dekker J;Taylor J;Corces VG
通讯作者：
Corces VG
DOI：
10.1126/science.1256271
发表时间：
2014-08-22
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Lara-Astiaso D;Weiner A;Lorenzo-Vivas E;Zaretsky I;Jaitin DA;David E;Keren-Shaul H;Mildner A;Winter D;Jung S;Friedman N;Amit I
通讯作者：
Amit I
影响因子：
16
作者：
Kaikkonen, Minna U.;Spann, Nathanael J.;Heinz, Sven;Romanoski, Casey E.;Allison, Karmel A.;Stender, Joshua D.;Chun, Hyun B.;Tough, David F.;Prinjha, Rab K.;Benner, Christopher;Glass, Christopher K.
通讯作者：
Glass, Christopher K.
影响因子：
21.3
作者：
通讯作者：
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