Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom.
The Francis Crick Institute, London, United Kingdom.
PLoS Genet. 2022 Jun 16;18(6):e1010230. doi: 10.1371/journal.pgen.1010230. eCollection 2022 Jun.
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 the cis-regulatory interaction landscape of the key neuro-developmental Paupar-Pax6 lncRNA-mRNA locus. The results define chromatin architecture changes associated with high Paupar-Pax6 expression in neurons and identify both promoter selective as well as shared cis-regulatory-promoter interactions involved in regulating Paupar-Pax6 co-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 candidate cis-regulatory elements to coordinate Paupar and Pax6 co-expression. We describe distinct roles for Paupar in Pax6 expression control and show that the Paupar DNA locus contains a TCF7L2 bound transcriptional silencer whilst the Paupar transcript can act as an activator of Pax6. 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.
中枢神经系统表达的长非编码 RNA（lncRNA）通常位于基因组中靠近参与转录调控的蛋白质编码基因附近。这些 lncRNA-蛋白质编码基因对在神经系统中经常具有时间和空间上的共表达，并预测共同调节神经元发育和功能。尽管其中一些 lncRNA 也结合并调节编码转录因子的活性，但控制邻近 lncRNA-蛋白质编码基因共表达的调节机制尚不清楚。在这里，我们使用高分辨率 NG Capture-C 来绘制关键神经发育 Paupar-Pax6 lncRNA-mRNA 基因座的顺式调控相互作用图谱。结果定义了与神经元中高 Paupar-Pax6 表达相关的染色质结构变化，并确定了参与调节 Paupar-Pax6 共表达的启动子选择性以及共享的顺式调控-启动子相互作用。我们发现 TCF7L2 转录因子，一种染色质结构的调节剂和 Wnt 信号通路的主要效应物，结合到这些候选顺式调控元件中的一部分，以协调 Paupar 和 Pax6 的共表达。我们描述了 Paupar 在 Pax6 表达控制中的不同作用，并表明 Paupar DNA 基因座包含 TCF7L2 结合的转录沉默子，而 Paupar 转录本可以作为 Pax6 的激活剂。我们的工作为控制大脑中邻近 lncRNA 和蛋白质编码基因共表达的染色质相互作用、信号通路和转录因子提供了重要的见解。
