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Repressive gene regulation synchronizes development with cellular metabolism

Cassidy, Justin J. and Bernasek, Sebastian M. and Bakker, Rachael and Giri, Ritika and Peláez, Nicolás and Eder, Bryan and Bobrowska, Anna and Bagheri, Neda and Nunes Amaral, Luis A. and Carthew, Richard W. (2019) Repressive gene regulation synchronizes development with cellular metabolism. Cell, 178 (4). pp. 980-992. ISSN 0092-8674. http://resolver.caltech.edu/CaltechAUTHORS:20190213-072757892

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.cell.2019.06.023DOIArticle
https://doi.org/10.1101/548032DOIDiscussion Paper
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=0
Funders:
Funding AgencyGrant Number
Chicago Biomedical ConsortiumUNSPECIFIED
Malkin FundUNSPECIFIED
Northwestern Data Science InitiativeUNSPECIFIED
John and Leslie McQuownUNSPECIFIED
NSFDMS-1764421
Simons Foundation597491
NIH Predoctoral FellowshipT32 GM008061
NIH Predoctoral FellowshipT32 CA080621
NIHP50 GM81892
NIHR35 GM118144
Rappaport FoundationUNSPECIFIED
Issue or Number:4
Record Number:CaltechAUTHORS:20190213-072757892
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20190213-072757892
Official Citation:Justin J. Cassidy, Sebastian M. Bernasek, Rachael Bakker, Ritika Giri, Nicolás Peláez, Bryan Eder, Anna Bobrowska, Neda Bagheri, Luis A. Nunes Amaral, Richard W. Carthew, Repressive Gene Regulation Synchronizes Development with Cellular Metabolism, Cell, Volume 178, Issue 4, 2019, Pages 980-992.e17, ISSN 0092-8674, https://doi.org/10.1016/j.cell.2019.06.023. (http://www.sciencedirect.com/science/article/pii/S0092867419306865)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:92863
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:13 Feb 2019 15:47
Last Modified:13 Aug 2019 21:48

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