Dynamics and Function of Distal Regulatory Elements during Neurogenesis and Neuroplasticity. Mus musculus

Gene regulation in mammals involves a complex interplay between promoter and distal regulatory elements that function in concert to drive precise spatio-temporal gene expression programs. However, the dynamics of distal gene regulatory elements and its function in transcriptional reprogramming that underlies neurogenesis and neuronal activity remain largely unknown. Here we use a combinatorial analysis of genomewide datasets for chromatin accessibility (FAIRE-Seq) and enhancer mark H3K27ac to reveal a highly dynamic nature of chromatin accessibility during neurogenesis that gets restricted to certain genomic regions as neurons acquire a post-mitotic, terminally differentiated state. We further reveal that the distal open regions serve as target sites of distinct transcription factors that function in a stage-specific manner to contribute to the transcriptional program underlying neuronal commitment and maturation. A prolonged NMDA-driven neural activity results in epigenetic reprogramming at a large number of distal regulatory elements as well as dramatic reorganization of super-enhancers that in turn mediate critical transcriptional responses. Taken together, these findings reveal dynamics of distal regulatory landscape during neurogenesis and uncover novel regulatory elements that function in concert with epigenetic mechanisms and transcription factors to generate transcriptome underlying neuronal development and function. Overall design: FAIRE-Seq and H3K27ac profiles for three stages on neuronal differentation viz. neuronal progenitors, day 1 neurons and day 10 neurons, were generated to understand the dynamics of accessible and ehancer chromatin landscape. Along with this we also generated RNASeq and H3K27ac profiles for day 10 neurons upon control and NMDA treatment.