BMBDG Seminar – Jennifer Mitchell

“Comparative epigenomics determines transcriptional regulatory codes in mammalian genomes,” by Jennifer Mitchell, Department of Cell and Systems Biology, University of Toronto.

Abstract: Non-coding transcriptional enhancers are critical for development, phenotype divergence during evolution and often mutated in disease contexts; however, even in well-studied cell types, the sequence code conferring enhancer activity remains unknown. Enhancers are key drivers of pluripotency maintenance and the reprogramming process; therefore, determining the repertoire of sequences and transcription factors that confer activity to these regions will provide a better understanding of the pluripotent state and reveal transcriptional control mechanisms that define cell identity. Attempts to construct synthetic enhancers using the binding sequences for known pluripotency master regulators reveal our knowledge gaps, as these sequences display activity that is 10 fold lower than an endogenous native enhancer. We used comparative epigenomics to identify conserved enhancers in naïve mouse and human embryonic stem cells. Machine learning revealed these conserved enhancers are enriched in a conserved repertoire of 70 different transcription factor binding sites (TFBS) including known and novel pluripotency regulators. Remarkably, using a diverse set of >10 TFBS from this repertoire was sufficient to construct short synthetic enhancers with activity comparable to native enhancers. We next used this approach to predict the TFBS repertoire for different lineage committed cells and identified embryonic enhancers conserved between mouse and human. These developmental enhancers are normally silenced in the adult but become reactivated in adult cancers.

Monday, December 7, 2020 at 2:30 pm. Join by Zoom.

Hosted by Dr. LeAnn Howe