Policarpi, C; (2016) A novel class of activity-regulated enhancers in mammalian neurons. Doctoral thesis , UCL (University College London).

Abstract

In neurons, adaptation to environmental stimuli depends on the regulated expression of specific genes that modulate neuronal plasticity. Fine-tuned transcription of these genes requires the cooperation of multiple mechanisms, including the functional interaction of promoters with distally located enhancers. To investigate how synaptic activity regulates gene transcription in vivo, we performed a genome-wide ChIPseq analysis of histone H3 acetylation at lysine residues 9 and 14 (H3K9K14ac) using somatosensory cortex of mice exposed to a novel enriched environment (NEE). NEE is a physiological mode of stimulation that combines sensory, cognitive and social stimuli. We found that Short INterspersed Elements (SINEs) located in proximity of activity-dependent genes became acetylated in response to NEE. I discovered that de novo acetylated SINEs bear epigenetic marks associated with enhancer function, bind TFIIIC transcription factor and are transcribed in response to synaptic activity in an RNAPIII-dependent manner. Importantly, I demonstrated that a transcript of a SINE located in proximity of the activity-dependent gene Fos interacts with RNAPII and is required for Fos expression. My study identifies SINE elements as a novel class of neuronal enhancers and highlights an unexpected functional relationship between RNAPII and RNAPIII transcription.

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