Chromatin interaction maps identify Wnt responsive cis -regulatory elements coordinating Paupar-Pax6 expression in neuronal cells
Chromatin interaction maps identify Wnt responsive cis -regulatory elements coordinating Paupar-Pax6 expression in neuronal cells
复制标题
染色质相互作用图谱识别协调神经元细胞中 Paupar-Pax6 表达的 Wnt 响应顺式调节元件
DOI：
10.1101/2021.05.18.442939
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Pavlaki I
中科院分区：
文献类型：
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作者：
Pavlaki I
中枢神经系统表达的长链非编码RNA（lncRNA）通常位于基因组中靠近参与转录控制的蛋白质编码基因的位置。这种lncRNA-蛋白质编码基因对在神经系统中经常在时间和空间上共表达，并且被预测一起作用以调节神经元发育和功能。尽管这些lncRNA中的一些也结合并调节所编码的转录因子的活性，但是控制相邻lncRNA-蛋白质编码基因的共表达的调节机制仍然不清楚。在这里，我们使用高分辨率NG Capture-C来绘制关键神经发育的Paupar-Pax 6lncRNA-mRNA位点的顺调控相互作用图。结果确定了与神经元中Paupar-Pax 6高表达相关的染色质结构变化，并确定了参与调节Paupar-Pax 6共表达的启动子选择性以及共享顺式调节启动子相互作用。我们发现，TCF 7 L2转录因子，一个染色质结构的调节因子和Wnt信号通路的主要效应子，结合到这些候选细胞凋亡调节元件的一个子集，以协调Paupar和Pax 6的共表达。我们描述了PauparinPax 6表达控制的不同作用，并表明PauparDNA位点含有TCF 7 L2结合的转录沉默子，而Paupar转录本可以作为Pax 6的激活因子。我们的工作提供了重要的见解染色质相互作用，信号通路和转录因子控制的共同表达的相邻lncRNA和蛋白质编码基因在大脑中。
Central nervous system-expressed long non-coding RNAs (lncRNAs) are often located in the genome close to protein coding genes involved in transcriptional control. Such lncRNA-protein coding gene pairs are frequently temporally and spatially co-expressed in the nervous system and are predicted to act together to regulate neuronal development and function. Although some of these lncRNAs also bind and modulate the activity of the encoded transcription factors, the regulatory mechanisms controlling co-expression of neighbouring lncRNA-protein coding genes remain unclear. Here, we used high resolution NG Capture-C to map thecis-regulatory interaction landscape of the key neuro-developmentalPaupar-Pax6lncRNA-mRNA locus. The results define chromatin architecture changes associated with highPaupar-Pax6expression in neurons and identify both promoter selective as well as sharedcis-regulatory-promoter interactions involved in regulatingPaupar-Pax6co-expression. We discovered that the TCF7L2 transcription factor, a regulator of chromatin architecture and major effector of the Wnt signalling pathway, binds to a subset of these candidatecis-regulatory elements to coordinatePauparandPax6co-expression. We describe distinct roles forPauparinPax6expression control and show that thePauparDNA locus contains a TCF7L2 bound transcriptional silencer whilst thePaupartranscript can act as an activator ofPax6. Our work provides important insights into the chromatin interactions, signalling pathways and transcription factors controlling co-expression of adjacent lncRNAs and protein coding genes in the brain.