Introduction

For lab journal club, I chose to present “Enhancer redundancy provides phenotypic robustness in mammalian development”. Some of my thoughts on the paper are below:

Methods

  • Started with ten limb enhancers. Deleted them one by one no effect
    • Expression similar to wildtype
  • Picked enhancers for two genes and deleted pairs of enhancers - effect
    • The two genes were gli3 and shox2
    • Pairs of deletions had effects on limb morphology
    • THey show that the pairs of enhancers act together in the same cells
    • The paired deletions show lower expression than the wildtype
  • Deleted pairs of enhancers on sensitized background
    • One allele had a deletion of gli3 or shox2
    • The other allele was either WT, one enhancer deletion, two enhancer deletion or another knockout of the gene.
    • The one allele deletion on this background was worse than the het deletion
    • The double enhancer deletion on this background was same as or close to the double gene deletion
    • DKO on sensitized background looked similar to double knockout of gene
  • Used a correlation framework to link enhancers to target genes
    • To answer how common is this redundancy in enhancer networks
    • Looked at h3k27ac mark and gene expression of target gene to identiy correlations
    • Developmentally expressed genes have more enhancers indicating redundancy

+ves

  • First study I believe to show redundancy in enhancers in vertebrates
  • The experiments showed a logical ordering and were clear

-ves

  • Don’t believe if the enhancer gene correlation framework results added much
    • could have been helpful if they had tested some of the predictions here

Interesting conclusions:

  • Why are these enhancers conserved?
    • Is the phenotype too gross for the single enhancer deletions
  • What is the impact on interpreting human enhancer mutations?
    • Can we interpret them one at a time still?
  • Did they test pairs of enhancers for other genes?