Gather Fabian, Rauleac Tudor, Akol Ipek, Arumugam Ganeshkumar, Fullio Camila L, Müller Teresa, Kleidonas Dimitrios, Geiss-Friedlander Ruth, Fischer Andre, Vlachos Andreas, Backofen Rolf, Vogel Tanja
Institute for Anatomy and Cell Biology, Department of Molecular Embryology, Faculty of Medicine, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany.
Spemann Graduate School of Biology and Medicine (SGBM), Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany.
Nucleic Acids Res. 2025 Jun 20;53(12). doi: 10.1093/nar/gkaf539.
Derailed gene expression programs within the developing nervous system, encompassing both transcriptional and post-transcriptional processes, can cause diverse neurodevelopmental diseases (NDD). The NDD FOXG1-syndrome lacks full understanding of the mechanistic role of its eponymous gene product. While it is known that FOXG1 acts in part at the chromatin by binding to regulative regions, it is unclear what factors control its presence at specific sites. Long non-coding RNAs (lncRNAs) can mediate site-directed transcription factor binding, but their potential role in FOXG1-syndrome has not been described. Here, we show that FOXG1 localisation is regulated at selected loci through the lncRNA Pantr1. We identified FOXG1 as an upstream transcriptional activator of Pantr1 in human and mice. Further, we discovered that FOXG1 has the ability to associate with RNAs. Both transcriptional regulation of Pantr1 by FOXG1 and binding of both partners build up a regulative network that impacts the localisation of FOXG1 at selected genomic loci. Specifically, Pantr1 facilitates cooperative presence of FOXG1/NEUROD1 at specific sites, and Pantr1 reduction leads to redistribution of FOXG1 to comparably more generic binding sites. The rescue of impaired dendritic outgrowth upon FOXG1 reduction by simultaneous overexpression of Pantr1 underlines the importance of the FOXG1/Pantr1 regulative network.
发育中的神经系统内的基因表达程序紊乱，包括转录和转录后过程，可导致多种神经发育疾病（NDD）。NDD中的FOXG1综合征对其同名基因产物的机制作用尚不完全清楚。虽然已知FOXG1部分通过与调控区域结合在染色质上发挥作用，但尚不清楚哪些因素控制其在特定位点的存在。长链非编码RNA（lncRNA）可以介导位点定向转录因子结合，但其在FOXG1综合征中的潜在作用尚未见报道。在这里，我们表明FOXG1的定位在选定的基因座上通过lncRNA Pantr1进行调控。我们在人和小鼠中鉴定出FOXG1是Pantr1的上游转录激活因子。此外，我们发现FOXG1具有与RNA结合的能力。FOXG1对Pantr1的转录调控以及两者的结合建立了一个调控网络，影响FOXG1在选定基因组位点的定位。具体而言，Pantr1促进FOXG1/NEUROD1在特定位点的协同存在，而Pantr1的减少导致FOXG1重新分布到相对更通用的结合位点。通过同时过表达Pantr1来挽救FOXG1减少时受损的树突生长，突出了FOXG1/Pantr1调控网络的重要性。
