Unique Immune Cell Coactivators Specify Locus Control Region Function and Cell Stage.
Unique Immune Cell Coactivators Specify Locus Control Region Function and Cell Stage.
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DOI：
10.1016/j.molcel.2020.10.036
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发表时间：
2020-12-03
期刊：
影响因子：
16
通讯作者：
Roeder RG
中科院分区：
文献类型：
--
作者：
Chu CS;Hellmuth JC;Singh R;Ying HY;Skrabanek L;Teater MR;Doane AS;Elemento O;Melnick AM;Roeder RG
基因座控制区（LCR）功能定义了细胞的身份，并在癌症等疾病中发挥关键作用，尽管驱动功能的结构成分和相关因素的层次结构还不完全清楚。在这里，我们表明，OCA-B，一个B细胞特异性辅激活剂的生发中心（GC）的形成必不可少的，形成了一个三元复合物与淋巴富集OCT 2和GC特异性MEF 2 B转录因子，这种复合物占据并激活LCR，调节BCL 6原癌基因，是独特的需要由正常和恶性GC B细胞。从机制上讲，通过OCA-B-MED 1相互作用，该复合物是介体与BCL 6启动子结合所必需的。密集平铺的CRISPRi筛选表明，只有与该三元复合物高度结合的LCR片段对其功能是必需的。我们的研究结果表明，一个密切联系的复杂的谱系和阶段特异性的因素收敛于特定的和高度必要的增强子元件，以驱动功能的细胞类型定义LCR。Chu & Hellyard等人揭示了一种涉及三元转录复合物OCA-B·OCT 2·MEF 2B的分级调控，该复合物由谱系特异性因子和阶段特异性因子组成，作为关键组分，利用LCR内的不同必需增强子元件，该元件对于及时诱导BCL 6是必需的，BCL 6是生发中心B细胞分化的主调节因子。
Locus control region (LCR) functions define cellular identity and play critical roles in diseases such as cancer, although the hierarchy of structural components and associated factors that drive functionality are incompletely understood. Here we show that OCA-B, a B cell-specific coactivator essential for germinal center (GC) formation, forms a ternary complex with the lymphoid-enriched OCT2 and GC-specific MEF2B transcription factors, and that this complex occupies and activates an LCR that regulates the BCL6 proto-oncogene and is uniquely required by normal and malignant GC B-cells. Mechanistically, through OCA-B-MED1 interactions, this complex is required for Mediator association with the BCL6 promoter. Densely tiled CRISPRi screening indicates that only LCR segments heavily bound by this ternary complex are essential for its function. Our results demonstrate how an intimately linked complex of lineage- and stage-specific factors converges on specific and highly essential enhancer elements to drive the function of a cell-type defining LCR. Chu & Hellmuth et al. reveal a hierarchical regulation involving a ternary transcriptional complex OCA-B•OCT2•MEF2B composed of both lineage- and stage-specific factors as a critical component utilizing distinct essential enhancer elements within the LCR essential for timely induction of BCL6, a master regulator for germinal center B-cell differentiation.
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影响因子：
64.5
作者：
El Khattabi L;Zhao H;Kalchschmidt J;Young N;Jung S;Van Blerkom P;Kieffer-Kwon P;Kieffer-Kwon KR;Park S;Wang X;Krebs J;Tripathi S;Sakabe N;Sobreira DR;Huang SC;Rao SSP;Pruett N;Chauss D;Sadler E;Lopez A;Nóbrega MA;Aiden EL;Asturias FJ;Casellas R
通讯作者：
Casellas R
影响因子：
50.3
作者：
Brescia P;Schneider C;Holmes AB;Shen Q;Hussein S;Pasqualucci L;Basso K;Dalla-Favera R
通讯作者：
Dalla-Favera R
影响因子：
64.5
作者：
Bhatt DM;Pandya-Jones A;Tong AJ;Barozzi I;Lissner MM;Natoli G;Black DL;Smale ST
通讯作者：
Smale ST
DOI：
10.1073/pnas.1600557113
发表时间：
2016-04-05
影响因子：
11.1
作者：
Hodson, Daniel J.;Shaffer, Arthur L.;Staudt, Louis M.
通讯作者：
Staudt, Louis M.
影响因子：
20.3
作者：
Huang, Chuanxin;Geng, Huimin;Melnick, Ari
通讯作者：
Melnick, Ari