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Ratio-based sensing of two transcription factors regulates the transit to differentiation

Bernasek, Sebastian M. and Boisclair Lachance, Jean-François and Peláez, Nicolás and Hur, Suzy S. J. and Bakker, Rachael and Navarro, Heliodoro Tejedor and Sanchez-Luege, Nicelio and Amaral, Luís A. N. and Bagheri, Neda and Rebay, Ilaria and Carthew, Richard W. (2018) Ratio-based sensing of two transcription factors regulates the transit to differentiation. . (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20211005-213153941

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Abstract

Cell state transitions are usually thought to be triggered by changes in the absolute concentrations of relevant transcription factors. In the Drosophila eye, the transcription factor Yan maintains cells in a progenitor state by repressing gene expression, while the Pointed transcription factor activates gene expression programs that promote photoreceptor specification. In this study we investigate how retinal cell state transitions are resolved by quantifying the expression dynamics of Yan and Pointed proteins. Despite extensive cell-to-cell variation in absolute concentrations of Yan and Pointed, progenitor cells maintain a relatively constant ratio of Pointed-to-Yan protein. A sustained change in the Pointed-to-Yan ratio accompanies the transition to photoreceptor fates. Genetic perturbations that disrupt the ratio produce photoreceptor specification defects, suggesting that transitions depend upon a sustained change in the ratio. A model based on the statistical physics of protein-DNA binding illustrates how ratiometric sensing could produce the changes in gene expression that underlie these cell state transitions. We propose that ratiometric control mechanisms facilitate regulation of developmental transitions by multiple transcription factors, and thereby make the transitions robust to fluctuations in absolute protein levels.


Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/430744DOIDiscussion Paper
https://doi.org/10.5281/zenodo.5520468DOICode
ORCID:
AuthorORCID
Bernasek, Sebastian M.0000-0002-1410-6178
Peláez, Nicolás0000-0001-9098-088X
Amaral, Luís A. N.0000-0002-3762-789X
Bagheri, Neda0000-0003-0146-4627
Carthew, Richard W.0000-0003-0343-0156
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license. This version posted October 4, 2021. We thank Kevin White’s lab and the MODEncode Consortium for recombineering the Pnt-GFP transgene, the Howard Hughes Medical Institute (N.P.), the Chicago Biomedical Consortium (N.P), the Robert Lurie Northwestern Cancer Center (N.P.), the NIH (EY025957, I.R. and R.W.C; GM118144, R.W.C.; GM080372, I.R.), the NSF (1764421, L.A.N.A., N.B. and R.W.C), and Simons Foundation (597491 L.A.N.A., N.B. and R.W.C) for funding, the Bloomington Drosophila Stock Center for flies, Laura Nilson for the use of computational resources, the Developmental Studies Hybridoma Bank for antibody reagents, and the Northwestern Biological Imaging Facility (BIF) for technical imaging support. The authors have declared no competing interest. Data and software availability: All segmented and annotated eye discs will be deposited in a data repository upon publication. A series of Jupyter notebooks that use these data to reproduce all analysis, simulations, and figures presented in this manuscript has also been made available (https://github.com/sbernasek/pnt_yan_ratio). The Silhouette app used to segment nuclei in eye discs expressing His-RFP and annotate nuclei in all eye discs is freely available via the macOS App Store, while the FlyEye python package used to generate, align, and visualize expression dynamics has been published on GitHub (https://doi.org/10.5281/zenodo.5520468).
Funders:
Funding AgencyGrant Number
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Chicago Biomedical ConsortiumUNSPECIFIED
Robert Lurie Northwestern Cancer CenterUNSPECIFIED
NIHEY025957
NIHGM118144
NIHGM080372
NSFDMS-1764421
Simons Foundation597491
Record Number:CaltechAUTHORS:20211005-213153941
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20211005-213153941
Official Citation:Ratio-based sensing of two transcription factors regulates the transit to differentiation. Sebastian M. Bernasek, Jean-Francois Boisclair Lachance, Nicolás Peláez, Suzy SJ Hur, Rachael Bakker, Heliodoro Tejedor Navarro, Nicelio Sanchez-Luege, Luis A. N. Amaral, Neda Bagheri, Ilaria Rebay, Richard W. Carthew. bioRxiv 430744; doi: https://doi.org/10.1101/430744
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:111225
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:05 Oct 2021 23:35
Last Modified:05 Oct 2021 23:35

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