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Developmental and housekeeping transcriptional programs display distinct modes of enhancer-enhancer cooperativity in Drosophila

Author

Listed:
  • Vincent Loubiere

    (Vienna BioCenter (VBC))

  • Bernardo P. Almeida

    (Vienna BioCenter (VBC)
    Doctoral School of the University of Vienna and Medical University of Vienna)

  • Michaela Pagani

    (Vienna BioCenter (VBC))

  • Alexander Stark

    (Vienna BioCenter (VBC)
    Vienna BioCenter (VBC))

Abstract

Genomic enhancers are key transcriptional regulators which, upon the binding of sequence-specific transcription factors, activate their cognate target promoters. Although enhancers have been extensively studied in isolation, a substantial number of genes have more than one simultaneously active enhancer, and it remains unclear how these cooperate to regulate transcription. Using Drosophila melanogaster S2 cells as a model, we assay the activities of more than a thousand individual enhancers and about a million enhancer pairs toward housekeeping and developmental core promoters with STARR-seq. We report that housekeeping and developmental enhancers show distinct modes of enhancer-enhancer cooperativity: while housekeeping enhancers are additive such that their combined activity mirrors the sum of their individual activities, developmental enhancers are super-additive and combine multiplicatively. Super-additivity between developmental enhancers is promiscuous and neither depends on the enhancers’ endogenous genomic contexts nor on specific transcription factor motif signatures. However, it can be further boosted by Twist and Trl motifs and saturates for the highest levels of enhancer activity. These results have important implications for our understanding of gene regulation in complex multi-enhancer developmental loci and genomically clustered housekeeping genes, providing a rationale to interpret the transcriptional impact of non-coding mutations at different loci.

Suggested Citation

  • Vincent Loubiere & Bernardo P. Almeida & Michaela Pagani & Alexander Stark, 2024. "Developmental and housekeeping transcriptional programs display distinct modes of enhancer-enhancer cooperativity in Drosophila," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52921-2
    DOI: 10.1038/s41467-024-52921-2
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    References listed on IDEAS

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    1. Evgeny Z. Kvon & Tomas Kazmar & Gerald Stampfel & J. Omar Yáñez-Cuna & Michaela Pagani & Katharina Schernhuber & Barry J. Dickson & Alexander Stark, 2014. "Genome-scale functional characterization of Drosophila developmental enhancers in vivo," Nature, Nature, vol. 512(7512), pages 91-95, August.
    2. Simon, Noah & Friedman, Jerome H. & Hastie, Trevor & Tibshirani, Rob, 2011. "Regularization Paths for Cox's Proportional Hazards Model via Coordinate Descent," Journal of Statistical Software, Foundation for Open Access Statistics, vol. 39(i05).
    3. Marco Osterwalder & Iros Barozzi & Virginie Tissières & Yoko Fukuda-Yuzawa & Brandon J. Mannion & Sarah Y. Afzal & Elizabeth A. Lee & Yiwen Zhu & Ingrid Plajzer-Frick & Catherine S. Pickle & Momoe Kat, 2018. "Enhancer redundancy provides phenotypic robustness in mammalian development," Nature, Nature, vol. 554(7691), pages 239-243, February.
    4. Drew T. Bergman & Thouis R. Jones & Vincent Liu & Judhajeet Ray & Evelyn Jagoda & Layla Siraj & Helen Y. Kang & Joseph Nasser & Michael Kane & Antonio Rios & Tung H. Nguyen & Sharon R. Grossman & Char, 2022. "Compatibility rules of human enhancer and promoter sequences," Nature, Nature, vol. 607(7917), pages 176-184, July.
    5. Gerald Stampfel & Tomáš Kazmar & Olga Frank & Sebastian Wienerroither & Franziska Reiter & Alexander Stark, 2015. "Transcriptional regulators form diverse groups with context-dependent regulatory functions," Nature, Nature, vol. 528(7580), pages 147-151, December.
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