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Diverse Hormone Response Networks in 41 Independent Drosophila Cell Lines
Marcus Stoiber1, Susan Celniker2, Lucy Cherbas3
1Department of Biostatistics, University of California Berkeley, California 94720 Department of Genome Dynamics, Lawrence Berkeley National Laboratory, California 94720.
Abstract:
Steroid hormones induce cascades of gene activation and repression with transformative effects on cell fate . Steroid transduction plays a major role in the development and physiology of nearly all metazoan species, and in the progression of the most common forms of cancer. Despite the paramount importance of steroids in developmental and translational biology, a complete map of transcriptional response has not been developed for any hormone . In the case of 20-hydroxyecdysone (ecdysone) in Drosophila melanogaster, these trajectories range from apoptosis to immortalization. We mapped the ecdysone transduction network in a cohort of 41 cell lines, the largest such atlas yet assembled. We found that the early transcriptional response mirrors the distinctiveness of physiological origins: genes respond in restricted patterns, conditional on the expression levels of dozens of transcription factors. Only a small cohort of genes is constitutively modulated independent of initial cell state. Ecdysone-responsive genes tend to organize into directional same-stranded units, with consecutive genes induced from the same strand. Here, we identify half of the ecdysone receptor heterodimer as the primary rate-limiting step in the response, and find that initial receptor isoform levels modulate the activated cohort of target transcription factors. This atlas of steroid response reveals organizing principles of gene regulation by a model type II nuclear receptor and lays the foundation for comprehensive and predictive understanding of the ecdysone transduction network in the fruit fly.
Insights
Researchers mapped the 20-hydroxyecdysone (ecdysone) gene network in 41 fruit fly cell lines. This steroid hormone response atlas reveals how initial cell states dictate gene activation, identifying key regulatory steps.
Area of Science:
- Molecular Biology
- Genomics
- Developmental Biology
Background:
- Steroid hormones regulate critical biological processes, including development and cancer progression.
- Understanding steroid hormone-induced gene networks is vital, yet incomplete for most hormones.
- The fruit fly hormone 20-hydroxyecdysone (ecdysone) triggers diverse cellular outcomes, from apoptosis to immortalization.
Purpose of the Study:
- To comprehensively map the ecdysone signal transduction network in Drosophila melanogaster.
- To identify the organizing principles governing gene regulation by ecdysone.
- To establish a foundation for predicting ecdysone's effects on gene expression.
Main Methods:
- Analysis of the ecdysone transduction network across 41 distinct fruit fly cell lines.
- Characterization of transcriptional response patterns conditional on initial cell states and transcription factor expression.
- Identification of rate-limiting steps and receptor isoform influences in the ecdysone response.
Main Results:
- The early transcriptional response to ecdysone is highly dependent on the cell's physiological origin and transcription factor landscape.
- A small subset of genes exhibits constitutive modulation, independent of the initial cell state.
- Ecdysone-responsive genes often form directional, same-stranded units.
- The ecdysone receptor heterodimer's subunit is identified as a primary rate-limiting factor.
Conclusions:
- The largest atlas of steroid response in fruit flies reveals context-dependent gene regulation.
- Initial ecdysone receptor levels significantly modulate downstream transcription factor activation.
- This work provides critical insights into type II nuclear receptor-mediated gene regulation.
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