XPQM-1 complements DAF-16 as a key transcriptional regulator of DAF-2-mediated development and longevity

Ronald G. Tepper; Jasmine Ashraf; Rachel Kaletsky; Gunnar Kleemann; Coleen T. Murphy; Harmen J. Bussemaker

doi:10.1016/j.cell.2013.07.006

XPQM-1 complements DAF-16 as a key transcriptional regulator of DAF-2-mediated development and longevity

Ronald G. Tepper, Jasmine Ashraf, Rachel Kaletsky, Gunnar Kleemann, Coleen T. Murphy, Harmen J. Bussemaker

Research output: Contribution to journal › Article › peer-review

213 Scopus citations

Abstract

Reduced insulin/IGF-1-like signaling (IIS) extends C elegans lifespan by upregulating stress response (class I) and downregulating other (class II) genes through a mechanism that depends on the conserved transcription factor DAF-16/FOXO. By integrating genome-wide mRNA expression responsiveness to DAF-16 with genome-wide in vivo binding data for a compendium of transcription factors, we discovered that PQM-1 is the elusive transcriptional activator that directly controls development (class II) genes by binding to the DAF-16-associated element (DAE). DAF-16 directly regulates class I genes only, through the DAF-16-binding element (DBE). Loss of PQM-1 suppresses daf-2 longevity and further slows development. Surprisingly, the nuclear localization of PQM-1 and DAF-16 is controlled by IIS in opposite ways and was also found to be mutually antagonistic. We observe progressive loss of nuclear PQM-1 with age, explaining declining expression of PQM-1 targets. Together, our data suggest an elegant mechanism for balancing stress response and development.

Original language	English (US)
Pages (from-to)	X676-690
Journal	Cell
Volume	154
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2013.07.006
State	Published - Aug 1 2013

All Science Journal Classification (ASJC) codes

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2013.07.006

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@article{01bd8e51b0064158809cbf31a81a5a7d,

title = "XPQM-1 complements DAF-16 as a key transcriptional regulator of DAF-2-mediated development and longevity",

abstract = "Reduced insulin/IGF-1-like signaling (IIS) extends C elegans lifespan by upregulating stress response (class I) and downregulating other (class II) genes through a mechanism that depends on the conserved transcription factor DAF-16/FOXO. By integrating genome-wide mRNA expression responsiveness to DAF-16 with genome-wide in vivo binding data for a compendium of transcription factors, we discovered that PQM-1 is the elusive transcriptional activator that directly controls development (class II) genes by binding to the DAF-16-associated element (DAE). DAF-16 directly regulates class I genes only, through the DAF-16-binding element (DBE). Loss of PQM-1 suppresses daf-2 longevity and further slows development. Surprisingly, the nuclear localization of PQM-1 and DAF-16 is controlled by IIS in opposite ways and was also found to be mutually antagonistic. We observe progressive loss of nuclear PQM-1 with age, explaining declining expression of PQM-1 targets. Together, our data suggest an elegant mechanism for balancing stress response and development.",

author = "Tepper, {Ronald G.} and Jasmine Ashraf and Rachel Kaletsky and Gunnar Kleemann and Murphy, {Coleen T.} and Bussemaker, {Harmen J.}",

note = "Funding Information: We thank the C. elegans Genetics Center, I. Hope, and S. Kim for strains; X.-J. Lu for implementing the REDUCE suite; M. Huynen for help with the phylogenetic analysis of the PQM-1 protein sequence; and M. Chalfie, I. Greenwald, O. Hobert, and members of the Bussemaker and Murphy laboratories, and the anonymous reviewers for valuable suggestions. This work was supported by NIH grants R01HG003008, U54CA121852, and P50GM071508, as well as a John Simon Guggenheim Foundation Fellowship to H.J.B., and by NIH Innovator award DP2OD004402 and R01AG034446 and grants from the Glenn and Keck Foundations to C.T.M. R.G.T. and H.J.B. performed all computational analyses; C.T.M. designed all C. elegans experiments; R.K. and J.A. performed DAE promoter binding experiments; G.K. and J.A. performed dauer recovery experiment; J.A. performed all remaining experiments; and R.G.T., H.J.B., and C.T.M. wrote the manuscript. ",

year = "2013",

month = aug,

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doi = "10.1016/j.cell.2013.07.006",

language = "English (US)",

volume = "154",

pages = "X676--690",

journal = "Cell",

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publisher = "Elsevier B.V.",

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TY - JOUR

T1 - XPQM-1 complements DAF-16 as a key transcriptional regulator of DAF-2-mediated development and longevity

AU - Tepper, Ronald G.

AU - Ashraf, Jasmine

AU - Kaletsky, Rachel

AU - Kleemann, Gunnar

AU - Murphy, Coleen T.

AU - Bussemaker, Harmen J.

N1 - Funding Information: We thank the C. elegans Genetics Center, I. Hope, and S. Kim for strains; X.-J. Lu for implementing the REDUCE suite; M. Huynen for help with the phylogenetic analysis of the PQM-1 protein sequence; and M. Chalfie, I. Greenwald, O. Hobert, and members of the Bussemaker and Murphy laboratories, and the anonymous reviewers for valuable suggestions. This work was supported by NIH grants R01HG003008, U54CA121852, and P50GM071508, as well as a John Simon Guggenheim Foundation Fellowship to H.J.B., and by NIH Innovator award DP2OD004402 and R01AG034446 and grants from the Glenn and Keck Foundations to C.T.M. R.G.T. and H.J.B. performed all computational analyses; C.T.M. designed all C. elegans experiments; R.K. and J.A. performed DAE promoter binding experiments; G.K. and J.A. performed dauer recovery experiment; J.A. performed all remaining experiments; and R.G.T., H.J.B., and C.T.M. wrote the manuscript.

PY - 2013/8/1

Y1 - 2013/8/1

N2 - Reduced insulin/IGF-1-like signaling (IIS) extends C elegans lifespan by upregulating stress response (class I) and downregulating other (class II) genes through a mechanism that depends on the conserved transcription factor DAF-16/FOXO. By integrating genome-wide mRNA expression responsiveness to DAF-16 with genome-wide in vivo binding data for a compendium of transcription factors, we discovered that PQM-1 is the elusive transcriptional activator that directly controls development (class II) genes by binding to the DAF-16-associated element (DAE). DAF-16 directly regulates class I genes only, through the DAF-16-binding element (DBE). Loss of PQM-1 suppresses daf-2 longevity and further slows development. Surprisingly, the nuclear localization of PQM-1 and DAF-16 is controlled by IIS in opposite ways and was also found to be mutually antagonistic. We observe progressive loss of nuclear PQM-1 with age, explaining declining expression of PQM-1 targets. Together, our data suggest an elegant mechanism for balancing stress response and development.

AB - Reduced insulin/IGF-1-like signaling (IIS) extends C elegans lifespan by upregulating stress response (class I) and downregulating other (class II) genes through a mechanism that depends on the conserved transcription factor DAF-16/FOXO. By integrating genome-wide mRNA expression responsiveness to DAF-16 with genome-wide in vivo binding data for a compendium of transcription factors, we discovered that PQM-1 is the elusive transcriptional activator that directly controls development (class II) genes by binding to the DAF-16-associated element (DAE). DAF-16 directly regulates class I genes only, through the DAF-16-binding element (DBE). Loss of PQM-1 suppresses daf-2 longevity and further slows development. Surprisingly, the nuclear localization of PQM-1 and DAF-16 is controlled by IIS in opposite ways and was also found to be mutually antagonistic. We observe progressive loss of nuclear PQM-1 with age, explaining declining expression of PQM-1 targets. Together, our data suggest an elegant mechanism for balancing stress response and development.

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U2 - 10.1016/j.cell.2013.07.006

DO - 10.1016/j.cell.2013.07.006

M3 - Article

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AN - SCOPUS:84881175076

SN - 0092-8674

VL - 154

SP - X676-690

JO - Cell

JF - Cell

IS - 3

ER -

XPQM-1 complements DAF-16 as a key transcriptional regulator of DAF-2-mediated development and longevity

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