Dynamics and function of distal regulatory elements during neurogenesis and neuroplasticity

Abstract

Gene regulation in mammals involves a complex interplay between promoters and distal regulatory elements that function in concert to drive precise spatiotemporal gene expression programs. However, the dynamics of the distal gene regulatory landscape and its function in the transcriptional reprogramming that underlies neurogenesis and neuronal activity remain largely unknown. Here, we performed a combinatorial analysis of genome-wide data sets for chromatin accessibility (FAIREseq) and the enhancer mark H3K27ac, revealing the highly dynamic nature of distal gene regulation during neurogenesis, which gets progressively restricted to distinct genomic regions as neurons acquire a post-mitotic, terminally differentiated state. We further find that the distal accessible and active regions serve as target sites for distinct transcription factors that function in a stage-specific manner to contribute to the transcriptional program underlying neuronal commitment and maturation. Mature neurons respond to a sustained activity of NMDA receptors by epigenetic reprogramming at a large number of distal regulatory regions as well as dramatic reorganization of super-enhancers. Such massive remodeling of the distal regulatory landscape in turn results in a transcriptome that confers a transient loss of neuronal identity and gain of cellular plasticity. Furthermore, NMDA receptor activity also induces many novel prosurvival genes that function in neuroprotective pathways. Taken together, these findings reveal the dynamics of the distal regulatory landscape during neurogenesis and uncover novel regulatory elements that function in concert with epigenetic mechanisms and transcription factors to generate the transcriptome underlying neuronal development and activity.

NRL-Regulated Transcriptome Dynamics of Developing Rod Photoreceptors

“…Neuronal cell type-specific analysis has been limited to heterogeneous transcriptome landscapes of discrete regions of the brain (Hawrylycz et al, 2012; Tebbenkamp et al, 2014) or stem cell-derived neurons (Kaewkhaw et al, 2015; Thakurela et al, 2015; van de Leemput et al, 2014). Only a few neuron-specific transcriptomes have been reported so far (Akimoto et al, 2006; Macosko et al, 2015; Siegert et al, 2012; Telley et al, 2016; Zhang et al, 2014).…”

Enhancer and super‐enhancer: Positive regulators in gene transcription

“…Analyses of the super‐enhancer dynamics during lineage commitment of specific cell types have shown that super‐enhancers are remodeled during differentiation, having crucial roles in cell fate determination . Deletion of super‐enhancer constituents at the Nanog or Sox2 locus in mouse embryonic stem cells reduces the corresponding target gene expression and impaired some other key pluripotency genes, resulting in cellular differentiation.…”

Gene–Environment Interplay and Individual Differences in Behavior

“…This most likely relates back to the findings in the animal literature that most phenotypes are driven by complex G×G, G×E interactions, and G–E correlations, rather than by single genes. Furthermore, when disease‐correlated SNPs fall outside of gene‐coding regions, they are often assumed to affect the gene with the closest proximity, while in truth they might be affecting the expression of a more distant gene (Thakurela, Sahu, Kumar, Garding, & Tiwari, ). Additionally, from the perspective of the present discussion, little is known about genetic differences and individual variation in normal human development that is not linked to a disease phenotype.…”