@article{d0d562e46fc74cf8b472c2dbe860ca80,
title = "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. microRNAs become dispensable for development in the context of slower metabolism.",
keywords = "Drosophila, control theory, development, mathematical modeling, metabolism, microRNA",
author = "Cassidy, {Justin J.} and Bernasek, {Sebastian M.} and Rachael Bakker and Ritika Giri and Nicol{\'a}s Pel{\'a}ez and B. Eder and Anna Bobrowska and Neda Bagheri and {Nunes Amaral}, {Luis A.} and Carthew, {Richard W.}",
note = "Funding Information: 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 yan transgene 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.). 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. Funding Information: 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 yan transgene 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.). Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = aug,
day = "8",
doi = "10.1016/j.cell.2019.06.023",
language = "English (US)",
volume = "178",
pages = "980--992.e17",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "4",
}