Repressive Gene Regulation Synchronizes Development with Cellular Metabolism

Justin J. Cassidy, Sebastian M. Bernasek, Rachael Bakker, Ritika Giri, Nicolás Peláez, B. Eder, Anna Bobrowska, Neda Bagheri, Luis A N Amaral*, Richard W Carthew

*Corresponding author for this work

Research output: Contribution to journalArticle

1 Citation (Scopus)

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. microRNAs become dispensable for development in the context of slower metabolism.

Original languageEnglish (US)
Pages (from-to)980-992.e17
JournalCell
Volume178
Issue number4
DOIs
StatePublished - Aug 8 2019

Fingerprint

Metabolism
Gene expression
Gene Regulatory Networks
Genes
MicroRNAs
Developmental Genes
Protein Stability
RNA Stability
Transcription
Drosophila
Animals
Theoretical Models
Mathematical models
Gene Expression
Messenger RNA
Proteins

Keywords

  • Drosophila
  • control theory
  • development
  • mathematical modeling
  • metabolism
  • microRNA

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Cassidy, J. J., Bernasek, S. M., Bakker, R., Giri, R., Peláez, N., Eder, B., ... Carthew, R. W. (2019). Repressive Gene Regulation Synchronizes Development with Cellular Metabolism. Cell, 178(4), 980-992.e17. https://doi.org/10.1016/j.cell.2019.06.023
Cassidy, Justin J. ; Bernasek, Sebastian M. ; Bakker, Rachael ; Giri, Ritika ; Peláez, Nicolás ; Eder, B. ; Bobrowska, Anna ; Bagheri, Neda ; Amaral, Luis A N ; Carthew, Richard W. / Repressive Gene Regulation Synchronizes Development with Cellular Metabolism. In: Cell. 2019 ; Vol. 178, No. 4. pp. 980-992.e17.
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Cassidy, JJ, Bernasek, SM, Bakker, R, Giri, R, Peláez, N, Eder, B, Bobrowska, A, Bagheri, N, Amaral, LAN & Carthew, RW 2019, 'Repressive Gene Regulation Synchronizes Development with Cellular Metabolism', Cell, vol. 178, no. 4, pp. 980-992.e17. https://doi.org/10.1016/j.cell.2019.06.023

Repressive Gene Regulation Synchronizes Development with Cellular Metabolism. / Cassidy, Justin J.; Bernasek, Sebastian M.; Bakker, Rachael; Giri, Ritika; Peláez, Nicolás; Eder, B.; Bobrowska, Anna; Bagheri, Neda; Amaral, Luis A N; Carthew, Richard W.

In: Cell, Vol. 178, No. 4, 08.08.2019, p. 980-992.e17.

Research output: Contribution to journalArticle

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AU - Bakker, Rachael

AU - Giri, Ritika

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AU - Eder, B.

AU - Bobrowska, Anna

AU - Bagheri, Neda

AU - Amaral, Luis A N

AU - Carthew, Richard W

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Cassidy JJ, Bernasek SM, Bakker R, Giri R, Peláez N, Eder B et al. Repressive Gene Regulation Synchronizes Development with Cellular Metabolism. Cell. 2019 Aug 8;178(4):980-992.e17. https://doi.org/10.1016/j.cell.2019.06.023