Histone modifications and chromatin remodeling represent universal mechanisms by which cells adapt their transcriptional response to rapidly changing environmental conditions. Extensive chromatin remodeling takes place during neuronal development, allowing the transition of pluripotent cells into differentiated neurons. Here, we report that the NuRD complex, which couples ATP-dependent chromatin remodeling with histone deacetylase activity, regulates mouse brain development. Subunit exchange of CHDs, the core ATPase subunits of the NuRD complex, is required for distinct aspects of cortical development. Whereas CHD4 promotes the early proliferation of progenitors, CHD5 facilitates neuronal migration and CHD3 ensures proper layer specification. Inhibition of each CHD leads to defects of neuronal differentiation and migration, which cannot be rescued by expressing heterologous CHDs. Finally, we demonstrate that NuRD complexes containing specific CHDs are recruited to regulatory elements and modulate the expression of genes essential for brain development.

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. In neurons, acetylation of histones and other epigenetic modifications influence gene expression in response to synaptic activity. 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. Here, we show a novel regulatory role for Short Interspersed Elements (SINEs) located in the proximity of activity-regulated genes. SINEs represent a new class of regulatory sequences that function as coordinators of depolarization-dependent transcription. Binding of the general transcription factor TFIIIC to SINEs regulates activity-dependent transcription, relocation of inducible genes to transcription factories and dendritogenesis. 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.

Spatiotemporal regulation of gene expression depends on the cooperation of multiple mechanisms, including the functional interaction of promoters with distally located enhancers. Here, we show that, in cortical neurons, a subset of short interspersed nuclear elements (SINEs) located in the proximity of activity-regulated genes bears features of enhancers. Enhancer SINEs (eSINEs) recruit the Pol III cofactor complex TFIIIC in a stimulus-dependent manner and are transcribed by Pol III in response to neuronal depolarization. Characterization of an eSINE located in proximity to the Fos gene (FosRSINE1) indicated that the FosRSINE1-encoded transcript interacts with Pol II at the Fos promoter and mediates Fos relocation to Pol II factories, providing an unprecedented molecular link between Pol III and Pol II transcription. Strikingly, knockdown of the FosRSINE1 transcript induces defects of both cortical radial migration in vivo and activity-dependent dendritogenesis in vitro, demonstrating that FosRSINE1 acts as a strong enhancer of Fos expression in diverse physiological contexts.

Significance: Epigenetic modifications of chromatin are emerging as important regulatory mechanisms of many nuclear processes. Numerous proteins have been identified that mediate these modifications in a dynamic manner. However, less is known about the signaling pathways that transduce upstream signals into chromatin changes. Here, we show that the signaling molecule inositol pyrophosphate (IP ₇ ) synthesised by inositol hexakisphosphate kinase 1 plays a key role in regulating the association of one of these proteins, Jumonji domain containing 2C with chromatin, thereby controlling the levels of a number of crucial epigenetic modifications important to regulate gene expression.