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Updated: Jun 16, 2025
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Quantitative Comparison of cis-Regulatory Element CRE Activities in Transgenic Drosophila melanogaster
Published on: December 19, 2011
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Conservation of regulatory elements with highly diverged sequences across large evolutionary distances
Mai H Q Phan1,2, Tobias Zehnder2, Fiona Puntieri2
1Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Center for Regenerative Therapies, Berlin, Germany.
Nature Genetics
|May 27, 2025
Summary
Most developmental gene regulatory elements (CREs) change rapidly over evolutionary time. However, this study reveals that many sequence-divergent CREs maintain function by remaining in conserved genomic positions.
Area of Science:
- Genomics
- Developmental Biology
- Evolutionary Biology
Background:
- Developmental gene expression is crucial for organism development and is highly conserved across species.
- Cis-regulatory elements (CREs), which control gene expression, often lack sequence conservation over evolutionary time, posing a challenge for understanding functional conservation.
- The degree to which CREs maintain function solely through conserved genomic location, independent of sequence, is not fully understood.
Purpose of the Study:
- To investigate the extent of functional conservation of cis-regulatory elements (CREs) in conserved genomic positions despite sequence divergence.
- To develop and apply novel computational methods for identifying positionally conserved CREs across species.
- To experimentally validate the function of identified indirectly conserved CREs.
Main Methods:
- Comparative genomics analysis of regulatory elements in mouse and chicken embryonic hearts.
- Development and application of the synteny-based algorithm 'interspecies point projection' to identify positionally conserved CREs.
- In vivo reporter assays in mouse embryos to validate the function of conserved chicken enhancers.
Main Results:
- The majority of cis-regulatory elements (CREs) show little to no sequence conservation between mouse and chicken.
- The 'interspecies point projection' algorithm identified significantly more positionally conserved CREs ('indirectly conserved' orthologs) than traditional alignment-based methods.
- Indirectly conserved CREs share chromatin and sequence composition similarities with sequence-conserved CREs, but exhibit greater transcription factor binding site turnover.
- In vivo validation confirmed the regulatory function of indirectly conserved enhancers.
Conclusions:
- Functional conservation of cis-regulatory elements (CREs) can be maintained through conserved genomic location, even with significant sequence divergence.
- Novel computational approaches like 'interspecies point projection' are essential for uncovering hidden functional conservation across evolutionary distances.
- This work expands our understanding of genome evolution and the mechanisms underlying conserved developmental processes.
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