Poised enhancers control the expression of key genes involved in brain development

03/27/2017

The team of Alvaro Rada-Iglesias has discovered that a group of DNA regulatory sequences, called poised enhancers, are essential for the induction of genes with major roles during brain development.

Moreover, they uncovered that this regulatory function involves a novel epigenetic mechanism whereby poised enhancers and their target genes are brought together into physical proximity within the cellular nucleus. Their work was recently published in the prestigious journal Cell Stem Cell.

Enhancers are short DNA sequences located outside genes that control when and where genes need to be expressed. Consequently, enhancer sequences play essential roles during development and their disruption can frequently contribute to human disease. Previous work from Dr. Rada-Iglesias while he was still a postdoc at Stanford University (USA) uncovered a novel and unique class of enhancers that were originally called poised enhancers (Rada-Iglesias, et al., Nature, 2011).

Poised enhancers were discovered in embryonic stem cells (ESC), which are considered to be pluripotent as they can give rise to any of the cell types that will eventually constitute an adult organism. Interestingly, although poised enhancers were already bookmarked in ESC, they only became active upon differentiation and, thus, were proposed to control the establishment of gene expression programs during mammalian development.

The discovery of poised enhancers was an important milestone in the field of gene regulation, but the functional relevance of poised enhancers and the mechanisms by which they control gene expression remained unknown. Recent work from Dr. Rada-Iglesias' group at the CMMC, including PhD students Sara de la Cruz Molina and Milos Nikolic and postdocs Patricia Respuela and Christina Tebartz, has shed light into these open questions:

  • Poised enhancers become preferentially activated in the anterior neural lineage, suggesting an important function during brain development.
  • Poised enhancers are essential for the induction of genes considered as major regulators of brain development.
  • To control the expression of their target genes, poised enhancers establish strong physical interactions with these genes. This involves a novel mechanism whereby a group of epigenetic regulators, called polycomb proteins, keep poised enhancers and their target genes close to each other within the cellular nucleus.
  • Poised enhancers contain genetic and epigenetic information that might be required to orchestrate the earliest steps of brain development.

Currently, Dr. Rada-Iglesias' team in collaboration with Dr. Hisham Bazzi (CECAD Cologne) is trying to elucidate whether poised enhancers are also functional in vivo during mouse embryogenesis. Moreover, Dr. Rada-Iglesias' team is exploring whether poised enhancers might also exist in other cell populations, such as adult stem cells, whose integrity is typically compromised during ageing and disease.

Original Publication:

Cruz-Molina S, Respuela P, Tebartz C, Kolovos P, Nikolic M, Fueyo R, van Ijcken W.F.J, Grosveld F, Frommolt P, Bazzi H, Rada-Iglesias A.
PRC2 facilitates the regulatory topology required for poised enhancer function during pluripotent stem cell differentiation. Cell Stem Cell. In press.

 

Dr. Alvaro Rada-Iglesias is leading a Junior Research Group at the CMMC and is associated PI at CECAD Cologne. The Junior Research Group Program is a funding program of the CMMC, which is comparable to the Emmy Noether-Program by the German research Foundation and equivalent to an Assistant Professorship (W1) with a running period of 5 (+3) years.

http://www.cmmc-uni-koeln.de/research/junior-research-groups/

 

 


For further information, please contact:
Alvaro Rada-Iglesias, PhD

Junior Research Group Leader - Lab. of Developmental Genomics Laboratory

Center for Molecular Medicine Cologne (CMMC), University of Cologne - Cologne, Germany
phone: +49 (0) 221 478 96 988

e-mail: aradaigl[at]uni-koeln.de

Alvaro Rada-Iglesias and the members of his research team

Schematic overview of the strategy used to evaluate the functional relevance of poised enhancers. CRISPR/Cas9 technology was used to generate ESC lines in which candidate poised enhancers were deleted. Then, the resulting ESC lines were differentiated into anterior neural progenitors to evaluate whether the poised enhancer deletions have any effects on gene expression.

Proposed model of poised enhancers’ function during the induction of major anterior neural genes.