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A Rapid In Vivo Bioassay for Developmentally Active Enhancers
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Spatial regulation by multiple Gremlin1 enhancers provides digit development with cis-regulatory robustness and
Jonas Malkmus1, Laurène Ramos Martins1, Shalu Jhanwar1,2
1Developmental Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland.
Nature Communications
|September 22, 2021
Summary
Understanding Gremlin1 (Grem1) gene regulation is key for limb development. Spatial control, not just quantity, of Grem1 expression is vital, impacting digit formation and evolution.
Area of Science:
- Developmental Biology
- Evolutionary Biology
- Genomics
Background:
- Precise gene expression control is crucial for embryogenesis and tissue development.
- Gremlin1 (Grem1), a BMP antagonist, is a key regulator of limb bud development.
Purpose of the Study:
- To identify enhancers in the Grem1 genomic landscape.
- To elucidate the cis-regulatory logic governing spatio-temporal Grem1 expression during limb development.
- To investigate the evolutionary conservation and plasticity of Grem1 regulation.
Main Methods:
- Mouse reverse genetics to identify Grem1 enhancers.
- Analysis of cis-regulatory interactions.
- Comparative genomics across species.
Main Results:
- Transcript levels are additively controlled, while spatial regulation depends on synergistic enhancer interactions.
- Disruption of synergistic interactions altered spatial Grem1 regulation, leading to digit fusions and loss, more so than reduced transcript levels.
- Two ancient, conserved enhancers were identified, showing spatial plasticity in Grem1 regulation from basal fishes to mammals.
Conclusions:
- Spatio-temporal Grem1 regulation is orchestrated by complex cis-regulatory logic involving synergistic enhancer activity.
- Altered spatial Grem1 expression, driven by disrupted enhancer interactions, is a critical factor in limb malformations.
- The evolutionary plasticity of Grem1 regulation offers insights into the fin-to-limb transition and vertebrate limb diversification.
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