Super-enhancers: drivers of cells’ identities and cells’ debacles

Abstract

Precise spatiotemporal regulations of gene expression are essential for determining cells’ fates and functions. Enhancers are cis-acting DNA elements that act as periodic transcriptional thrusters and their activities are cell type specific. Clusters of enhancers, called super-enhancers, are more densely occupied by transcriptional activators than enhancers, driving stronger expression of their target genes, which have prominent roles in establishing and maintaining cellular identities. Here we review the current knowledge on the composition and structure of super-enhancers to understand how they robustly stimulate the expression of cellular identity genes. We also review their involvement in the development of various cell types and both noncancerous and cancerous disorders, implying the therapeutic interest of targeting them to fight against various diseases.

Tweetable abstract

Super-enhancers orchestrate expressions of genes that shape cells’ identity, whether this identity is physiological or malignant. This review is a compendium of current knowledge. #epigenetic #superenhancers #cellsidentity

Executive summary

Super-enhancers: structure & functionality

• Super-enhancers (SEs), which are epigenetic elements, dictate the expression of genes that shape cells’ identity, whether this identity is physiological or pathological.

• They are composed via a regrouping of enhancers which may have different roles and importance.

• SEs are marked by various post-translational modifications of histones, which decompress chromatin torsions.

• SEs massively concentrate transcription factors through a liquid–liquid phase separation reaction. This phenomenon creates protranscriptional macromolecular condensates at SEs/target gene loci. They are assembled and dismantled in a few seconds.

• SEs exert their power on the expression of their target genes thanks to physical proximity. This power is limited by the precise 3D organization of the chromatin.

The future of super-enhancers

• Cutting-edge technologies enable the precise mapping of chromatin contacts at the nucleotide scale and the precise nuclear geolocation of different elements at the protein scale. These technologies enable SEs to be studied in detail on a case-by-case basis while simultaneously studying thousands of SEs.

• These technologies are becoming increasingly sophisticated, enabling us to continually refine our knowledge of SEs.

• Given the important role played by SEs in the normal and abnormal development of cells, SEs are promising targets in the fight against various diseases. Thus, epidrugs (molecules targeting epigenetic processes) have a bright future ahead of them.

Keywords: :

• cell identity
• chromatin organization
• epidrugs
• histone marks
• master transcription factors
• multimolecular condensates
• seRNAs
• super-enhancers
• topologically associated domains

Author contributions

M Lavaud wrote this manuscript. R Tesfaye revised this manuscript. S Georges, L Lassous, B Brounais, M Baud'huin, F Verrecchia and F Lamoureux gave their advice for this manuscript. B Ory chaperoned and revised this manuscript. All the authors have read and approved the final manuscript.

Financial disclosure

The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.