Activation of the Notch Signaling Pathway In Vivo Elicits Changes in CSL Nuclear Dynamics.
Activation of the Notch Signaling Pathway In Vivo Elicits Changes in CSL Nuclear Dynamics.
复制标题
DOI：
10.1016/j.devcel.2018.01.020
复制
发表时间：
2018-03-12
影响因子：
11.8
通讯作者：
Bray SJ
中科院分区：
文献类型：
--
作者：
Gomez-Lamarca MJ;Falo-Sanjuan J;Stojnic R;Abdul Rehman S;Muresan L;Jones ML;Pillidge Z;Cerda-Moya G;Yuan Z;Baloul S;Valenti P;Bystricky K;Payre F;O'Holleran K;Kovall R;Bray SJ
Notch 信号传导的一个关键特征是，它通过 DNA 结合因子 CSL 指导转录的立即变化，将其从抑制转变为激活。在没有任何扩增步骤的情况下，Notch 如何产生灵敏且准确的响应仍有待阐明。为了解决这个问题，我们开发了 CSL 动态的实时分析，包括体内单分子跟踪。在Notch-OFF核中，一小部分CSL分子短暂结合DNA，而在Notch-ON条件下，CSL在目标位点的募集显着增加，其中复合物由Notch共激活剂Mastermind赋予更长的停留时间。令人惊讶的是，在 Notch-ON 条件下，CSL 相关辅阻遏物的募集也会增加，这表明 Notch 通过促进染色质可及性的局部增加来诱导合作或“辅助”加载。因此，体内Notch活动会触发CSL停留时间和染色质可及性的变化，我们建议这赋予对微小输入变化的敏感性并促进及时关闭。实时成像显示，CSL 在 Notch-OFF 条件下非常动态地结合。Notch-ON 细胞中 CSL 的募集增强，并且其停留时间增加。Notch 局部增加了染色质可及性，以促进 CSL 复合物的加载。Notch 共激活剂 Mastermind Gomez-Lamarca 等人赋予了更长的 CSL 停留时间。通过对关键 DNA 结合因子 CSL 进行体内实时分析，探索转录水平上 Notch 信号反应的基础。 CSL 具有高度动态性，DNA 短暂停留在 Notch-OFF 状态。 Notch 活性增加了染色质的可及性，并赋予响应敏感性更长的停留时间。
A key feature of Notch signaling is that it directs immediate changes in transcription via the DNA-binding factor CSL, switching it from repression to activation. How Notch generates both a sensitive and accurate response—in the absence of any amplification step—remains to be elucidated. To address this question, we developed real-time analysis of CSL dynamics including single-molecule tracking in vivo. In Notch-OFF nuclei, a small proportion of CSL molecules transiently binds DNA, while in Notch-ON conditions CSL recruitment increases dramatically at target loci, where complexes have longer dwell times conferred by the Notch co-activator Mastermind. Surprisingly, recruitment of CSL-related corepressors also increases in Notch-ON conditions, revealing that Notch induces cooperative or “assisted” loading by promoting local increase in chromatin accessibility. Thus, in vivo Notch activity triggers changes in CSL dwell times and chromatin accessibility, which we propose confer sensitivity to small input changes and facilitate timely shut-down. Live imaging reveals that CSL binds very dynamically in Notch-OFF conditions Recruitment of CSL is enhanced in Notch-ON cells, and its residence time is increased Notch locally increases chromatin accessibility to promote loading of CSL complexes Longer CSL dwell times are conferred by the Notch-co-activator Mastermind Gomez-Lamarca et al. explore the basis of Notch signaling responsiveness at the transcriptional level through in vivo, real-time analysis of key DNA-binding factor CSL. CSL is highly dynamic with transient DNA residence in the Notch-OFF state. Notch activity increases chromatin accessibility and confers a longer dwell time for response sensitivity.
登录
查看更多内容
影响因子：
3.4
作者：
Beaudouin, JL;Mora-Bermúdez, F;Ellenberg, J
通讯作者：
Ellenberg, J
DOI：
10.1109/tpami.2013.97
发表时间：
2013-11-01
影响因子：
23.6
作者：
Chenouard, Nicolas;Bloch, Isabelle;Olivo-Marin, Jean-Christophe
通讯作者：
Olivo-Marin, Jean-Christophe
Notch配体delta1的密度决定了造血干细胞的B和T细胞前体的产生。
影响因子：
15.3
作者：
Dallas, MH;Varnum- Finney, B;Delaney, C;Kato, K;Bernstein, ID
通讯作者：
Bernstein, ID
SPDAMID：通过蛋白质复合物结合的DNA标记可识别Notch-Dimer响应式增强子。
影响因子：
16
作者：
Hass MR;Liow HH;Chen X;Sharma A;Inoue YU;Inoue T;Reeb A;Martens A;Fulbright M;Raju S;Stevens M;Boyle S;Park JS;Weirauch MT;Brent MR;Kopan R
通讯作者：
Kopan R
影响因子：
10.5
作者：
Fryer, CJ;Lamar, E;Jones, KA
通讯作者：
Jones, KA