Abstract
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.
Highlights
The adaptation of living organisms to their surroundings depends on their ability to fine-tune their behaviors in response to novel conditions
Genes that are concomitantly expressed in response to stimulation are transcribed at specific nuclear foci, known as transcription factories (TFs) that are enriched with active RNA Polymerase II and often include specific transcription factors
Our study provides new fundamental insights into the mechanisms by which relocation of inducible genes to transcription factories and changes of nuclear architecture coordinate the transcriptional program in response to neuronal activity
Summary
The adaptation of living organisms to their surroundings depends on their ability to fine-tune their behaviors in response to novel conditions. Exposure to environmental enrichment correlates with a number of morphological changes, ranging from increased dendritic growth and branching to enhanced synaptogenesis and hippocampal neurogenesis [1]. Many of these enrichment-mediated cellular changes depend on the expression of specific genes involved in neuronal plasticity, such as the neurotrophins Brain Derived Neurotrophic Factor (BDNF) and Nerve Growth Factor (NGF), as well as synaptic proteins, including PSD95 and glutamate receptor subunits [2,3,4]. Interaction of co-activators with specific DNA sequences within gene promoters is associated with stimulusdependent transcription [6]. Transcriptional activators and repressors are often simultaneously detected on promoters of both active and inactive genes [7], suggesting that a dynamic balance between gene activation and inhibition may determine the transcriptional outcome
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