Multimodal epigenetic changes and altered NEUROD1 chromatin binding in the mouse hippocampus underlie FOXG1 syndrome

The data presented in this study enlighten for the first time in a comprehensive manner diverse and multi-modal functions of FOXG1 at the chromatin level in mature neurons. Despite FOXG1 being recognized as a key transcription factor for telencephalic development and neuronal function, insights into the mechanism underlying transcriptional regulation are sparse. We here show that (i) FOXG1 acts both as repressor and activator, (ii) localizes predominantly to enhancer regions, (iii) alters the epigenetic landscape, (iv) affects directly HDAC functions, and (v) acts in concert with NEUROD1 to instruct transcriptional programs necessary for axono- and synaptogenesis. Bulk RNA-seq was performed in hippocampal tissue isolated from Foxg1cre/+ and Foxg1+/+ mice.

本研究的数据首次全面阐明了FOXG1在成熟神经元染色质层面的多样化多模态功能。尽管FOXG1已被公认为端脑发育与神经元功能的关键转录因子，但目前学界对其转录调控背后的分子机制仍知之甚少。本研究在此展示了五项核心发现：(1) FOXG1同时兼具转录阻遏与激活双重功能；(2) 其主要定位于增强子区域；(3) 能够重塑表观遗传景观；(4) 直接影响HDAC（组蛋白去乙酰化酶）的功能；(5) 可与NEUROD1协同作用，指导轴突发生与突触发生所需的转录程序。研究人员对分离自Foxg1cre/+与Foxg1+/+小鼠的海马组织开展了批量RNA测序（bulk RNA-seq）实验。