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
染色质相互作用图识别Wnt响应的顺式调节元件，可在神经元细胞中协调PAUPAR-PAX6表达。
DOI：
10.1371/journal.pgen.1010230
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发表时间：
2022-06
期刊：
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
--
作者：
中枢神经系统表达的长非编码RNA(LncRNAs)通常位于基因组中，靠近参与转录调控的蛋白质编码基因。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，并被预测为共同调节神经元的发育和功能。虽然其中一些lncRNA也结合并调节编码转录因子的活性，但控制相邻lncRNA-蛋白质编码基因共表达的调控机制仍不清楚。在这里，我们使用高分辨率的NG Capture-C来绘制关键的神经发育Paupar-Pax6 lncRNA-mRNA基因座的顺式调控相互作用图谱。这些结果确定了与Paupar-Pax6在神经元中高表达相关的染色质结构变化，并确定了参与调节Paupar-Pax6共同表达的启动子选择性和共享性顺式调节-启动子相互作用。我们发现，TCF7L2转录因子是染色质结构的调节因子，也是Wnt信号通路的主要效应者，它与这些候选顺式调节元件的子集结合，以协调Paupar和Pax6的共同表达。我们描述了Paupar在Pax6表达调控中的不同作用，并表明Paupar DNA位点包含一个TCF7L2结合的转录沉默因子，而Paupar转录本可以作为Pax6的激活因子。我们的工作为了解染色质相互作用、信号通路和转录因子控制大脑中相邻lncRNAs和蛋白质编码基因的共同表达提供了重要的见解。长非编码RNA(LncRNA)基因通常在大脑中与邻近的参与基因表达调控的蛋白质编码基因共表达。据预测，这种lncRNA-蛋白质编码基因对将共同调节神经元的发育和功能。尽管如此，人们对控制它们共同表达的调控机制知之甚少。在这里，我们确定了染色质的相互作用和DNA序列控制Paupar-Pax6lncRNA-蛋白质编码区在大脑中的表达。我们发现，Wnt信号通路是发育和疾病的关键调节因子，通过TCF7L2转录因子协调它们的表达。我们发现Paupar DNA包含沉默Pax6的序列，而Paupar RNA可以作为Pax6的激活剂。我们的工作为控制邻近lncRNA-蛋白质编码基因功能的复杂调控关系提供了新的见解，并对理解大脑的发育非常重要。
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. Long non-coding RNA (lncRNA) genes are often co-expressed in the brain with neighbouring protein coding genes involved in gene expression control. Such lncRNA-protein coding gene pairs are predicted to work together to regulate neuronal development and function. Despite this, the regulatory mechanisms controlling their co-expression is poorly understood. Here, we identify the chromatin interactions and DNA sequences controlling expression of the Paupar-Pax6 lncRNA-protein coding locus in the brain. We show that the Wnt signalling pathway, a key regulator of development and disease, acts through the TCF7L2 transcription factor to co-ordinate their expression. We find that Paupar DNA contains sequences that silence Pax6 whilst the Paupar RNA can act as an activator of Pax6. Our work generates new insights into the complex regulatory relationship controlling the function of neighbouring lncRNA-protein coding genes and is important for understanding development of the brain.
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影响因子：
7.7
作者：
Freire-Pritchett P;Schoenfelder S;Várnai C;Wingett SW;Cairns J;Collier AJ;García-Vílchez R;Furlan-Magaril M;Osborne CS;Fraser P;Rugg-Gunn PJ;Spivakov M
通讯作者：
Spivakov M
影响因子：
4.3
作者：
Irastorza-Azcarate I;Acemel RD;Tena JJ;Maeso I;Gómez-Skarmeta JL;Devos DP
通讯作者：
Devos DP
影响因子：
30.8
作者：
JORDAN, T;HANSON, I;VANHEYNINGEN, V
通讯作者：
VANHEYNINGEN, V
影响因子：
4
作者：
Gerrard, Diana L.;Wang, Yao;Frietze, Seth E.
通讯作者：
Frietze, Seth E.
影响因子：
7.7
作者：
Hezroni, Hadas;Perry, Rotem B-T;Ulitsky, Igor
通讯作者：
Ulitsky, Igor