Dynamics and heterogeneity of a fate determinant during transition towards cell differentiation

Peláez, Nicolás; Gavalda-Miralles, Arnau; Wang, Bao; Navarro, Heliodoro Tejedor; Gudjonson, Herman; Rebay, Ilaria; Dinner, Aaron R.; Katsaggelos, Aggelos K.; Amaral, Luís AN; Carthew, Richard W.

doi:10.7554/eLife.08924

Title: Dynamics and heterogeneity of a fate determinant during transition towards cell differentiation

Abstract

Yan is an ETS-domain transcription factor responsible for maintaining Drosophila eye cells in a multipotent state. Yan is at the core of a regulatory network that determines the time and place in which cells transit from multipotency to one of several differentiated lineages. Using a fluorescent reporter for Yan expression, we observed a biphasic distribution of Yan in multipotent cells, with a rapid inductive phase and slow decay phase. Transitions to various differentiated states occurred over the course of this dynamic process, suggesting that Yan expression level does not strongly determine cell potential. Consistent with this conclusion, perturbing Yan expression by varying gene dosage had no effect on cell fate transitions. However, we observed that as cells transited to differentiation, Yan expression became highly heterogeneous and this heterogeneity was transient. Signals received via the EGF Receptor were necessary for the transience in Yan noise since genetic loss caused sustained noise. As a result, since these signals are essential for eye cells to differentiate, we suggest that dynamic heterogeneity of Yan is a necessary element of the transition process, and cell states are stabilized through noise reduction.

Authors:: Peláez, Nicolás; Gavalda-Miralles, Arnau; Wang, Bao; Navarro, Heliodoro Tejedor; Gudjonson, Herman; Rebay, Ilaria; Dinner, Aaron R.; Katsaggelos, Aggelos K.; Amaral, Luís AN; Carthew, Richard W.

Publication Date:: Thu Nov 19 00:00:00 EST 2015

Research Org.:: Northwestern Univ., Evanston, IL (United States)

Sponsoring Org.:: USDOE National Nuclear Security Administration (NNSA)

OSTI Identifier:: 1234765

Alternate Identifier(s):: OSTI ID: 1234766; OSTI ID: 1257261

Grant/Contract Number:: NA0002520

Resource Type:: Published Article

Journal Name:: eLife

Additional Journal Information:: Journal Name: eLife Journal Volume: 4; Journal ID: ISSN 2050-084X

Publisher:: eLife Sciences Publications, Ltd.

Country of Publication:: United States

Language:: English

Subject:: 59 BASIC BIOLOGICAL SCIENCES

Citation Formats


                    Peláez, Nicolás, Gavalda-Miralles, Arnau, Wang, Bao, Navarro, Heliodoro Tejedor, Gudjonson, Herman, Rebay, Ilaria, Dinner, Aaron R., Katsaggelos, Aggelos K., Amaral, Luís AN, and Carthew, Richard W. Dynamics and heterogeneity of a fate determinant during transition towards cell differentiation.  United States: N. p., 2015. 
Web.  doi:10.7554/eLife.08924.

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                    Peláez, Nicolás, Gavalda-Miralles, Arnau, Wang, Bao, Navarro, Heliodoro Tejedor, Gudjonson, Herman, Rebay, Ilaria, Dinner, Aaron R., Katsaggelos, Aggelos K., Amaral, Luís AN, & Carthew, Richard W. Dynamics and heterogeneity of a fate determinant during transition towards cell differentiation.  United States.  https://doi.org/10.7554/eLife.08924

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                    Peláez, Nicolás, Gavalda-Miralles, Arnau, Wang, Bao, Navarro, Heliodoro Tejedor, Gudjonson, Herman, Rebay, Ilaria, Dinner, Aaron R., Katsaggelos, Aggelos K., Amaral, Luís AN, and Carthew, Richard W. Thu .  
"Dynamics and heterogeneity of a fate determinant during transition towards cell differentiation".  United States.  https://doi.org/10.7554/eLife.08924.

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@article{osti_1234765,

  title        = {Dynamics and heterogeneity of a fate determinant during transition towards cell differentiation},

  author       = {Peláez, Nicolás and Gavalda-Miralles, Arnau and Wang, Bao and Navarro, Heliodoro Tejedor and Gudjonson, Herman and Rebay, Ilaria and Dinner, Aaron R. and Katsaggelos, Aggelos K. and Amaral, Luís AN and Carthew, Richard W.},

  abstractNote = {Yan is an ETS-domain transcription factor responsible for maintaining Drosophila eye cells in a multipotent state. Yan is at the core of a regulatory network that determines the time and place in which cells transit from multipotency to one of several differentiated lineages. Using a fluorescent reporter for Yan expression, we observed a biphasic distribution of Yan in multipotent cells, with a rapid inductive phase and slow decay phase. Transitions to various differentiated states occurred over the course of this dynamic process, suggesting that Yan expression level does not strongly determine cell potential. Consistent with this conclusion, perturbing Yan expression by varying gene dosage had no effect on cell fate transitions. However, we observed that as cells transited to differentiation, Yan expression became highly heterogeneous and this heterogeneity was transient. Signals received via the EGF Receptor were necessary for the transience in Yan noise since genetic loss caused sustained noise. As a result, since these signals are essential for eye cells to differentiate, we suggest that dynamic heterogeneity of Yan is a necessary element of the transition process, and cell states are stabilized through noise reduction.},

  doi          = {10.7554/eLife.08924},

  journal      = {eLife},

  number       = ,

  volume       = 4,

  place        = {United States},

  year         = {Thu Nov 19 00:00:00 EST 2015},

  month        = {Thu Nov 19 00:00:00 EST 2015}

}

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Title: Dynamics and heterogeneity of a fate determinant during transition towards cell differentiation

Abstract

Citation Formats

Consecutive Positive Feedback Loops Create a Bistable Switch that Controls Preadipocyte-to-Adipocyte Conversion journal, October 2012

Neuronal differentiation in the Drosophila ommatidium journal, April 1987

Overlapping Activators and Repressors Delimit Transcriptional Response to Receptor Tyrosine Kinase Signals in the Drosophila Eye journal, September 2000

Reciprocal inhibition between Pax7 and muscle regulatory factors modulates myogenic cell fate determination journal, June 2007

Statistical Mechanics of Pluripotency journal, August 2013

Wingless Signaling in Drosophila Eye Development book, January 2008

The regulation and functions of MAPK pathways in Drosophila journal, June 2014

A comparative study of Pointed and Yan expression reveals new complexity to the transcriptional networks downstream of receptor tyrosine kinase signaling journal, January 2014

Combinatorial Signaling in the Specification of Unique Cell Fates journal, September 2000

Deconstructing transcriptional heterogeneity in pluripotent stem cells journal, December 2014

Ras Pathway Specificity Is Determined by the Integration of Multiple Signal-Activated and Tissue-Restricted Transcription Factors journal, September 2000

Evidence that Fold-Change, and Not Absolute Level, of β-Catenin Dictates Wnt Signaling journal, December 2009

Development of the Drosophila retina, a neurocrystalline lattice journal, October 1976

The Incoherent Feedforward Loop Can Provide Fold-Change Detection in Gene Regulation journal, December 2009

atonal is the proneural gene for Drosophila photoreceptors journal, June 1994

Gene expression heterogeneities in embryonic stem cell populations: origin and function journal, December 2011

Ligand-dependent activation of breathless FGF receptor gene in Drosophila developing trachea journal, June 2002

Nkx6 Transcription Factors and Ptf1a Function as Antagonistic Lineage Determinants in Multipotent Pancreatic Progenitors journal, June 2010

Signalling by the sevenless protein tyrosine kinase is mimicked by Rasl activation journal, February 1992

A gain-of-function mutation in Drosophila MAP kinase activates multiple receptor tyrosine kinase signaling pathways journal, March 1994

Modeling bistable cell-fate choices in the Drosophila eye: qualitative and quantitative perspectives journal, June 2010

Homothorax Switches Function of Drosophila Photoreceptors from Color to Polarized Light Sensors journal, October 2003

The Relationship Between Long-Range Chromatin Occupancy and Polymerization of the Drosophila ETS Family Transcriptional Repressor Yan journal, November 2012

Positive Feedback Between PU.1 and the Cell Cycle Controls Myeloid Differentiation journal, July 2013

The activities of two Ets-related transcription factors required for drosophila eye development are modulated by the Ras/MAPK pathway journal, July 1994

Fractal dynamics in physiology: Alterations with disease and aging journal, February 2002

Ras1 signaling and transcriptional competence in the R7 cell of Drosophila. journal, September 1996

Threshold responses to morphogen gradients by zero‐order ultrasensitivity journal, January 2005

Mutations affecting the pattern of the larval cuticle inDrosophila melanogaster: II. Zygotic loci on the third chromosome journal, January 1984

Cell-type-specific transcription of prospero is controlled by combinatorial signaling in the Drosophila eye journal, July 2008

Transcriptome-wide noise controls lineage choice in mammalian progenitor cells journal, May 2008

Characterization of the Drosophila segment determination morphome journal, January 2008

A bistable Rb–E2F switch underlies the restriction point journal, March 2008

Origins and implications of pluripotent stem cell variability and heterogeneity journal, May 2013

Negative control of photoreceptor development in Drosophila by the product of the yan gene, an ETS domain protein journal, August 1992

Reiterative Use of the EGF Receptor Triggers Differentiation of All Cell Types in the Drosophila Eye journal, November 1996

Multilineage Transcriptional Priming and Determination of Alternate Hematopoietic Cell Fates journal, August 2006

Yan functions as a general inhibitor of differentiation and is negatively regulated by activation of the Ras1/MAPK pathway journal, June 1995

A MicroRNA Imparts Robustness against Environmental Fluctuation during Development journal, April 2009

Dynamics of Dpp Signaling and Proliferation Control journal, March 2011

Dynamics and Variability of ERK2 Response to EGF in Individual Living Cells journal, December 2009

Regulation of gene function: A comparison of enzyme activity levels in relation to gene dosage in diploids and triploids of Drosophila melanogaster journal, May 1973

Hedgehog directly controls initiation and propagation of retinal differentiation in the Drosophila eye journal, December 1997

Transcription factor heterogeneity in pluripotent stem cells: a stochastic advantage journal, May 2014

Cell clones and pattern formation: On the lineage of photoreceptor cells in the compound eye ofDrosophila journal, January 1977

Ommatidial development in Drosophila eye disc fragments journal, October 1986

Consecutive Positive Feedback Loops Create a Bistable Switch that Controls Preadipocyte-to-Adipocyte Conversion
journal, October 2012

Neuronal differentiation in the Drosophila ommatidium
journal, April 1987

Overlapping Activators and Repressors Delimit Transcriptional Response to Receptor Tyrosine Kinase Signals in the Drosophila Eye
journal, September 2000

Reciprocal inhibition between Pax7 and muscle regulatory factors modulates myogenic cell fate determination
journal, June 2007

Statistical Mechanics of Pluripotency
journal, August 2013

Wingless Signaling in Drosophila Eye Development
book, January 2008

The regulation and functions of MAPK pathways in Drosophila
journal, June 2014

A comparative study of Pointed and Yan expression reveals new complexity to the transcriptional networks downstream of receptor tyrosine kinase signaling
journal, January 2014

Combinatorial Signaling in the Specification of Unique Cell Fates
journal, September 2000

Deconstructing transcriptional heterogeneity in pluripotent stem cells
journal, December 2014

Ras Pathway Specificity Is Determined by the Integration of Multiple Signal-Activated and Tissue-Restricted Transcription Factors
journal, September 2000

Evidence that Fold-Change, and Not Absolute Level, of β-Catenin Dictates Wnt Signaling
journal, December 2009

Development of the Drosophila retina, a neurocrystalline lattice
journal, October 1976

The Incoherent Feedforward Loop Can Provide Fold-Change Detection in Gene Regulation
journal, December 2009

atonal is the proneural gene for Drosophila photoreceptors
journal, June 1994

Gene expression heterogeneities in embryonic stem cell populations: origin and function
journal, December 2011

Ligand-dependent activation of breathless FGF receptor gene in Drosophila developing trachea
journal, June 2002

Nkx6 Transcription Factors and Ptf1a Function as Antagonistic Lineage Determinants in Multipotent Pancreatic Progenitors
journal, June 2010

Signalling by the sevenless protein tyrosine kinase is mimicked by Rasl activation
journal, February 1992

A gain-of-function mutation in Drosophila MAP kinase activates multiple receptor tyrosine kinase signaling pathways
journal, March 1994

Modeling bistable cell-fate choices in the Drosophila eye: qualitative and quantitative perspectives
journal, June 2010

Homothorax Switches Function of Drosophila Photoreceptors from Color to Polarized Light Sensors
journal, October 2003

The Relationship Between Long-Range Chromatin Occupancy and Polymerization of the Drosophila ETS Family Transcriptional Repressor Yan
journal, November 2012

Positive Feedback Between PU.1 and the Cell Cycle Controls Myeloid Differentiation
journal, July 2013

The activities of two Ets-related transcription factors required for drosophila eye development are modulated by the Ras/MAPK pathway
journal, July 1994

Fractal dynamics in physiology: Alterations with disease and aging
journal, February 2002

Ras1 signaling and transcriptional competence in the R7 cell of Drosophila.
journal, September 1996

Threshold responses to morphogen gradients by zero‐order ultrasensitivity
journal, January 2005

Mutations affecting the pattern of the larval cuticle inDrosophila melanogaster: II. Zygotic loci on the third chromosome
journal, January 1984

Cell-type-specific transcription of prospero is controlled by combinatorial signaling in the Drosophila eye
journal, July 2008

Transcriptome-wide noise controls lineage choice in mammalian progenitor cells
journal, May 2008

Characterization of the Drosophila segment determination morphome
journal, January 2008

A bistable Rb–E2F switch underlies the restriction point
journal, March 2008

Origins and implications of pluripotent stem cell variability and heterogeneity
journal, May 2013

Negative control of photoreceptor development in Drosophila by the product of the yan gene, an ETS domain protein
journal, August 1992

Reiterative Use of the EGF Receptor Triggers Differentiation of All Cell Types in the Drosophila Eye
journal, November 1996

Multilineage Transcriptional Priming and Determination of Alternate Hematopoietic Cell Fates
journal, August 2006

Yan functions as a general inhibitor of differentiation and is negatively regulated by activation of the Ras1/MAPK pathway
journal, June 1995

A MicroRNA Imparts Robustness against Environmental Fluctuation during Development
journal, April 2009

Dynamics of Dpp Signaling and Proliferation Control
journal, March 2011

Dynamics and Variability of ERK2 Response to EGF in Individual Living Cells
journal, December 2009

Regulation of gene function: A comparison of enzyme activity levels in relation to gene dosage in diploids and triploids of Drosophila melanogaster
journal, May 1973

Hedgehog directly controls initiation and propagation of retinal differentiation in the Drosophila eye
journal, December 1997

Transcription factor heterogeneity in pluripotent stem cells: a stochastic advantage
journal, May 2014

Cell clones and pattern formation: On the lineage of photoreceptor cells in the compound eye ofDrosophila
journal, January 1977

Ommatidial development in Drosophila eye disc fragments
journal, October 1986