Expression of Terminal Effector Genes in Mammalian Neurons Is Maintained by a Dynamic Relay of Transient Enhancers.
Expression of Terminal Effector Genes in Mammalian Neurons Is Maintained by a Dynamic Relay of Transient Enhancers.
复制标题
DOI：
10.1016/j.neuron.2016.11.037
复制
发表时间：
2016-12-21
期刊：
影响因子：
16.2
通讯作者：
Wichterle H
中科院分区：
文献类型：
--
作者：
Rhee HS;Closser M;Guo Y;Bashkirova EV;Tan GC;Gifford DK;Wichterle H
通用的脊髓运动神经元的身份是通过编程转录因子（TF），Isl 1和Lhx 3，运动神经元特异性增强子的合作结合建立的。在成熟神经元中编程转录因子下调后，效应基因的表达如何维持仍然未知。高分辨率核酸外切酶（ChIP-exo）图谱显示，大多数通过编程TF建立的增强子在干细胞来源的轴下运动神经元中Lhx 3下调后迅速失活。Isl 1从新生运动神经元增强子中释放出来，并被成熟神经元中Onecut 1簇结合的新增强子招募。合成增强子报告基因分析显示，Isl 1作为一个整合因子，翻译成瞬时增强子活性的Lhx 3或Onecut 1结合位点的密度。重要的是，独立的Isl 1/Lhx 3-和Isl 1/Onecut 1结合增强子有助于运动神经元效应基因的持续表达，表明有丝分裂后神经元中末端效应基因的向外稳定表达是由阶段特异性增强子的动态中继控制的。Rhee等人对新生和成熟ESC衍生的运动神经元中的TF结合进行了高分辨率全基因组分析。该研究揭示了Isl 1在动态增强子处整合阶段特异性TF以维持神经元细胞身份的机制。
Generic spinal motor neuron identity is established by cooperative binding of programming transcription factors (TFs), Isl1 and Lhx3, to motor-neuron-specific enhancers. How expression of effector genes is maintained following downregulation of programming TFs in maturing neurons remains unknown. High-resolution exonuclease (ChIP-exo) mapping revealed that the majority of enhancers established by programming TFs are rapidly deactivated following Lhx3 downregulation in stem-cell-derived hypaxial motor neurons. Isl1 is released from nascent motor neuron enhancers and recruited to new enhancers bound by clusters of Onecut1 in maturing neurons. Synthetic enhancer reporter assays revealed that Isl1 operates as an integrator factor, translating the density of Lhx3 or Onecut1 binding sites into transient enhancer activity. Importantly, independent Isl1/Lhx3- and Isl1/Onecut1-bound enhancers contribute to sustained expression of motor neuron effector genes, demonstrating that outwardly stable expression of terminal effector genes in postmitotic neurons is controlled by a dynamic relay of stage-specific enhancers. Rhee et al. performed high-resolution genome-wide analysis of TF binding in nascent and maturing ESC-derived motor neurons. The study revealed mechanisms by which Isl1 integrates stage-specific TFs at dynamic enhancers to maintain neuronal cell identity.
登录
查看更多内容
影响因子：
16
作者：
Calo, Eliezer;Wysocka, Joanna
通讯作者：
Wysocka, Joanna
影响因子：
3.3
作者：
Francius, C.;Clotman, F.
通讯作者：
Clotman, F.
影响因子：
14.9
作者：
Bailey TL;Johnson J;Grant CE;Noble WS
通讯作者：
Noble WS
影响因子：
4.3
作者：
Guo Y;Mahony S;Gifford DK
通讯作者：
Gifford DK
影响因子：
16.2
作者：
Novitch, BG;Chen, AI;Jessell, TM
通讯作者：
Jessell, TM