DECK 5: Super-Enhancers & Core Regulatory Circuitry

To understand super-enhancers as a concept and their application in cancer research. This is a more advanced topic that shows you understand current research applications.

When did super-enhancers become prominent?

2013

What defines a super-enhancer?

Broad regions highly enriched in transcription factor binding sites (TFBS)

How do super-enhancers compare to typical enhancers?

Broader, more TFBS, more tissue-specific activity

What features are used to identify super-enhancers?

H3K27ac or Med1 (Mediator complex) binding

What is a "core regulatory circuitry" network?

The key transcription factors that control cell fate in a given cell type

How are core regulatory circuitry maps generated?

Assess motifs in super-enhancers and identify which TF-coding genes they regulate

What cancer type was studied using super-enhancer mapping?

Rhabdomyosarcoma

What is the genetic driver of this rhabdomyosarcoma?

Translocation between PAX3-FOXO1 (or PAX7-FOXO1)

What does the PAX3-FOXO1 fusion do?

Directs transcriptional activity of one factor with localisation of another

How do super-enhancers relate to this fusion?

Core regulatory circuitry TFs drive expression of the fusion through super-enhancer looping

Why are these core TFs therapeutic targets?

They drive the oncogenic fusion expression

What publication defined super-enhancers?

Whyte et al., Cell, 2013

How are ranked enhancers used to identify super-enhancers?

Plotting enhancer signal (e.g., H3K27ac) reveals a sharp transition point