Repressive gene regulation synchronizes development with cellular metabolism
Abstract
Metabolic conditions affect the developmental tempo of animals. Developmental gene regulatory networks (GRNs) must therefore synchronize their dynamics with a variable timescale. We find that layered repression of genes couples GRN output with variable metabolism. When repressors of transcription or mRNA and protein stability are lost, fewer errors in Drosophila development occur when metabolism is lowered. We demonstrate the universality of this phenomenon by eliminating the entire microRNA family of repressors and find that development to maturity can be largely rescued when metabolism is reduced. Using a mathematical model that replicates GRN dynamics, we find that lowering metabolism suppresses the emergence of developmental errors by curtailing the influence of auxiliary repressors on GRN output. We experimentally show that gene expression dynamics are less affected by loss of repressors when metabolism is reduced. Thus, layered repression provides robustness through error suppression and may provide an evolutionary route to a shorter reproductive cycle.
Additional Information
© 2019 Elsevier Inc. Received 13 February 2019, Revised 6 May 2019, Accepted 12 June 2019, Available online 25 July 2019. We thank Jon Braverman for discussions and insights and the Bloomington Drosophila Stock Center and the Developmental Studies Hybridoma Bank for reagents. We also thank Alec Victorsen and Jennifer Moran for help with yantransgene recombineering and Diana Posadas and Hemanth Potluri for help with sens transgene recombineering. Jessica Hornick and the Biological Imaging Facility are acknowledged. We acknowledge support from the Chicago Biomedical Consortium (to J.J.C. and N.P.), the Malkin Foundation and Rappaport Foundation(to J.J.C.), the Northwestern Data Science Initiative (to R.G.), a John and Leslie McQuown gift (to L.A.N.A.), the NSF (1764421 to L.A.N.A., N.B., and R.W.C.), the Simons Foundation (597491 to L.A.N.A., N.B., and R.W.C), and the NIH (T32 GM008061 to J.J.C. and B.E., T32 CA080621 to R.B., and P50 GM81892 and R35 GM118144 to R.W.C.). Author Contributions: The experimental work was conceived by J.J.C. and R.W.C. The genetic experiments classifying phenotypes were performed by J.J.C., B.E., and A.B. under the supervision of R.W.C. N.P. designed and built the Yan-YFPΔmiR-7 mutant line, and R.B. performed imaging and analysis of Yan-YFP expression with assistance from S.M.B. and under the guidance of R.W.C. R.G. built the sfGFP-sens wild-type and mutant stocks with RpS13 and performed all imaging and analysis of sfGFP-Sens expression. The modeling was conceived by S.M.B., N.B., and L.A.N.A. All model analyses were performed by S.M.B. under the supervision of N.B. and L.A.N.A. The manuscript was written by S.M.B. and R.W.C. with input from all authors. The authors declare no competing interests. Data Availability: The phenotype datasets generated and/or analyzed during the current study are available from the corresponding authors on request. The dataset of all model simulations: https://arch.library.northwestern.edu/concern/generic_works/n296wz31t The Yan-YFP dataset: https://arch.library.northwestern.edu/concern/generic_works/n296wz31t The sfGFP-Sens dataset: https://www.dropbox.com/sh/1m9silkrs76rvpr/AADunGcGUylP2rQ9WRo5bXVha?dl=0 Code Availability: All code is publicly available at: Modeling and analysis: https://github.com/sebastianbernasek/GRaM Pipeline for Eye Silhouette imaging analysis: https://www.silhouette.amaral.northwestern.edu/ Older pipeline for imaging analysis: https://www.dropbox.com/s/62i91i17c9ja1c5/Pipeline_eye_eLife.zip?dl=0Attached Files
Accepted Version - nihms-1535146.pdf
Submitted - 548032.full.pdf
Supplemental Material - 1-s2.0-S0092867419306865-mmc1.pdf
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Additional details
- PMCID
- PMC6865806
- Eprint ID
- 92863
- Resolver ID
- CaltechAUTHORS:20190213-072757892
- Chicago Biomedical Consortium
- Malkin Fund
- Northwestern Data Science Initiative
- John and Leslie McQuown
- DMS-1764421
- NSF
- 597491
- Simons Foundation
- T32 GM008061
- NIH Predoctoral Fellowship
- T32 CA080621
- NIH Predoctoral Fellowship
- P50 GM81892
- NIH
- R35 GM118144
- NIH
- Rappaport Foundation
- Created
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2019-02-13Created from EPrint's datestamp field
- Updated
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2023-06-01Created from EPrint's last_modified field