Epigenetic and transcriptional regulation of neuronal circuit development and maturation

This seminar will be held on Microsoft Teams. Please join with your video off and mikes muted. Email hod-pa@dpag.ox.ac.uk for more details.

Appropriate transcriptional responses to environmental stimuli are fundamental for cellular development and maturation. In developing sensory neurons, neuronal activity-response genes are induced at birth by sensory experience, which drives neuronal maturation. In this seminar, firstly I will talk about how chromatin states regulate this transcriptional program during development. To address this issue, we isolated barrelette neurons (whisker-associated sensory neurons) from developing mouse hindbrains in wild-type and activity-deprived conditions using ad hoc genetic tools, and carried out chromatin and transcriptional profiling. We found that prior to perinatal induction immediate early genes (IEGs) are embedded into a unique ‘bipartite’ Polycomb chromatin signature. Namely, they carry active H3K27ac on promoters and enhancers, but repressive Ezh2-dependent H3K27me3 on gene bodies. This bipartite chromatin signature is not only found in neurons but it is widely present in developing cell types, including embryonic stem cells, and originates from bivalent chromatin. Polycomb marking of gene bodies inhibits productive mRNA elongation resulting in immature transcripts of bipartite genes, despite active promoters and enhancers, dampening basal productive transcription while maintaining their potential for fast induction. We revealed an epigenetic mechanism regulating the rapidity and amplitude of the transcriptional response to relevant stimuli, while preventing inappropriate activation of stimulus response genes and downstream cellular maturation programs.

Lastly, I will also briefly introduce about my future research project, in which I aim to decipher the developmental and molecular basis how a spatially intermingled and homogeneous neuronal population generates heterogeneous identities regarding circuit wring. To achieve this research goal, I will develop a novel retrospective genomics approach to overcome a critical bottleneck of the current snapshot-type of sequencing technologies.