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

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.

Contribution of 3D Chromatin Architecture to the Maintenance of Pluripotency

“…This is consistent with numerous studies linking transcriptional co-regulation to spatial clustering of the relevant genes and their cis-regulatory elements [26][27][28][29][30][31][32] around the nucleoplasmic supra-molecular entities that harbor most nuclear transcription-around transcription factories [19].…”

Conserved Higher-Order Chromatin Regulates NMDA Receptor Gene Expression and Cognition

“…Consistent with the definition of a classical promoter/enhancer loop—defined by the mobilization of conserved DNA elements into close proximity of a TSS to facilitate transcription(Ong and Corces, 2011)—the higher order chromatin structures described here were specific for cells expressing GRIN2B , with dynamic co-regulation of loopings and expression in the context of differentiation and increased synaptic activity. It remains to be determined whether these changes in chromosomal conformations occur independently, or in context with other activity-regulated changes in neuronal nuclei, including plasticity in nuclear geometry (Wittmann et al, 2009), mobilization of transcribed genes away from the nuclear lamina and other repressive environments (Walczak et al, 2013), and repositioning into subnuclear territories enriched with the transcriptional initiation complex(Crepaldi et al, 2013) and highly transcribed genes such as the (nuclear encoded) cytochrome c oxidase subunits(Dhar et al, 2009). Furthermore, according to genome-wide estimates, five independent enhancers could regulate the same TSS (Andersson et al, 2014), and therefore is it possible that GRIN2B expression is governed by the two long-range loops described here and additional regulatory sequences positioned 5’ or 3’ from the TSS.…”

The physics of epigenetics

“…(adapted from (Tumbar et al, 1999)) (b) A human cell nucleus. DNA is labeled in blue, PolII in red (from (Crepaldi et al, 2013)) yeast chromosomes behave as a polymer brush, and are essentially organized by simple physical principles (Huet et al, 2014) (see Fig. 3d,g).…”