Binding of TFIIIC to SINE Elements Controls the Relocation of Activity-Dependent Neuronal Genes to Transcription Factories

In neurons, the timely and accurate expression of genes in response to synaptic activity relies on the interplay between epigenetic modifications of histones, recruitment of regulatory proteins to chromatin and changes to nuclear structure. To identify genes and regulatory elements responsive to synaptic activation in vivo, we performed a genome-wide ChIPseq analysis of acetylated histone H3 using somatosensory cortex of mice exposed to novel enriched environmental (NEE) conditions. We discovered that Short Interspersed Elements (SINEs) located distal to promoters of activity-dependent genes became acetylated following exposure to NEE and were bound by the general transcription factor TFIIIC. Importantly, under depolarizing conditions, inducible genes relocated to transcription factories (TFs), and this event was controlled by TFIIIC. Silencing of the TFIIIC subunit Gtf3c5 in non-stimulated neurons induced uncontrolled relocation to TFs and transcription of activity-dependent genes. Remarkably, in cortical neurons, silencing of Gtf3c5 mimicked the effects of chronic depolarization, inducing a dramatic increase of both dendritic length and branching. These findings reveal a novel and essential regulatory function of both SINEs and TFIIIC in mediating gene relocation and transcription. They also suggest that TFIIIC may regulate the rearrangement of nuclear architecture, allowing the coordinated expression of activity-dependent neuronal genes.在神经元中，响应突触活动的基因得以及时且精准地表达，这依赖于组蛋白表观遗传修饰、调控蛋白向染色质的招募以及核结构变化之间的相互作用。为了在活体中鉴定响应突触激活的基因及调控元件，我们利用暴露于新颖丰富环境（NEE）的小鼠躯体感觉皮层，开展了全基因组范围的乙酰化组蛋白H3染色质免疫共沉淀测序（ChIPseq）分析。我们发现，位于活动依赖型基因启动子远端的短散在重复序列（SINEs）在暴露于NEE后发生乙酰化，并被通用转录因子IIIC（TFIIIC）结合。尤为重要的是，在去极化条件下，可诱导基因会移位至转录工厂（TFs），这一过程受TFIIIC调控。在未受刺激的神经元中沉默TFIIIC亚基Gtf3c5，会导致活动依赖型基因不受控地移位至转录工厂并发生转录。值得注意的是，在皮层神经元中，沉默Gtf3c5可模拟慢性去极化的效应，显著增加树突长度与分支数量。这些发现揭示了短散在重复序列（SINEs）与转录因子IIIC（TFIIIC）在介导基因移位与转录过程中的全新且关键的调控功能。同时，该研究也提示TFIIIC可能通过调控核结构重排，实现活动依赖型神经元基因的协同表达。