Limits...
The Caenorhabditis elegans Myc-Mondo/Mad complexes integrate diverse longevity signals.

Johnson DW, Llop JR, Farrell SF, Yuan J, Stolzenburg LR, Samuelson AV - PLoS Genet. (2014)

Bottom Line: Furthermore, decreased insulin-like/IGF-1 signaling (ILS) or conditions of dietary restriction increase the accumulation of MML-1, consistent with the notion that the Myc family members function as sensors of metabolic status.We compared putative target genes based on ChIP-sequencing data in the modENCODE project and found significant overlap in genomic DNA binding between the major effectors of ILS (DAF-16/FoxO), DR (PHA-4/FoxA), and Myc family (MDL-1/Mad/Mxd) at common target genes, which suggests that diverse signals of metabolic status converge on overlapping transcriptional programs that influence aging.Additionally, we find that Myc family members are also involved in stress response and the maintenance of protein homeostasis.

View Article: PubMed Central - PubMed

Affiliation: University of Rochester, Department of Biomedical Genetics, Rochester, New York, United States of America.

ABSTRACT
The Myc family of transcription factors regulates a variety of biological processes, including the cell cycle, growth, proliferation, metabolism, and apoptosis. In Caenorhabditis elegans, the "Myc interaction network" consists of two opposing heterodimeric complexes with antagonistic functions in transcriptional control: the Myc-Mondo:Mlx transcriptional activation complex and the Mad:Max transcriptional repression complex. In C. elegans, Mondo, Mlx, Mad, and Max are encoded by mml-1, mxl-2, mdl-1, and mxl-1, respectively. Here we show a similar antagonistic role for the C. elegans Myc-Mondo and Mad complexes in longevity control. Loss of mml-1 or mxl-2 shortens C. elegans lifespan. In contrast, loss of mdl-1 or mxl-1 increases longevity, dependent upon MML-1:MXL-2. The MML-1:MXL-2 and MDL-1:MXL-1 complexes function in both the insulin signaling and dietary restriction pathways. Furthermore, decreased insulin-like/IGF-1 signaling (ILS) or conditions of dietary restriction increase the accumulation of MML-1, consistent with the notion that the Myc family members function as sensors of metabolic status. Additionally, we find that Myc family members are regulated by distinct mechanisms, which would allow for integrated control of gene expression from diverse signals of metabolic status. We compared putative target genes based on ChIP-sequencing data in the modENCODE project and found significant overlap in genomic DNA binding between the major effectors of ILS (DAF-16/FoxO), DR (PHA-4/FoxA), and Myc family (MDL-1/Mad/Mxd) at common target genes, which suggests that diverse signals of metabolic status converge on overlapping transcriptional programs that influence aging. Consistent with this, there is over-enrichment at these common targets for genes that function in lifespan, stress response, and carbohydrate metabolism. Additionally, we find that Myc family members are also involved in stress response and the maintenance of protein homeostasis. Collectively, these findings indicate that Myc family members integrate diverse signals of metabolic status, to coordinate overlapping metabolic and cytoprotective transcriptional programs that determine the progression of aging.

Show MeSH

Related in: MedlinePlus

Model for Myc-Mondo/Mad transcription factors in longevity control under basal conditions the Myc-Mondo activation complex (MML-1:MXL-2) is largely inactive, and transcription of genes encoding functions related to aging is limited by the Mad transcriptional repression complex (MDL-1:MXL-1).Conditions of reduced ILS and DR promote Myc-Mondo complex activity, likely by regulating cellular localization and transcription of mml-1. Myc-Mondo/Mad transcription factors may cooperate with DAF-16 and PHA-4 to modulate the expression of key metabolic and cytoprotective genes to influence aging.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3974684&req=5

pgen-1004278-g008: Model for Myc-Mondo/Mad transcription factors in longevity control under basal conditions the Myc-Mondo activation complex (MML-1:MXL-2) is largely inactive, and transcription of genes encoding functions related to aging is limited by the Mad transcriptional repression complex (MDL-1:MXL-1).Conditions of reduced ILS and DR promote Myc-Mondo complex activity, likely by regulating cellular localization and transcription of mml-1. Myc-Mondo/Mad transcription factors may cooperate with DAF-16 and PHA-4 to modulate the expression of key metabolic and cytoprotective genes to influence aging.

Mentions: The Myc family of transcription factors have well established functions in growth control and metabolic regulation; processes that are known to influence lifespan. Yet, this is the first study to identify a role for the Myc interaction network in longevity control and proteostasis. We have identified a role for the Myc-family of bHLH transcription factors: mml-1, mdl-1, mxl-1, and mxl-2 in the regulation of C. elegans lifespan. We show that the Myc-Mondo (MML-1:MXL-2) and Mad (MDL-1:MXL-1) transcriptional complexes have opposing roles in longevity control and proteostasis analogous to their known functions as transcriptional activators and repressors in C. elegans[11]. Specifically, loss of the Myc-Mondo complex leads to premature aging, while loss of the Mad complex delays aging. Lifespan extension by loss of the Mad complex is dependent upon the Myc-Mondo complex, daf-16, and pha-4, suggesting a common mechanism in longevity control. Conversely, Myc-Mondo is required for lifespan extension by decreased ILS or conditions of DR. Both decreased ILS and conditions of DR promote nuclear accumulation of MML-1, but do so through distinct mechanisms; altered DAF-16 activity regulates expression of Myc family members, while pha-4 is essential for the increased nuclear accumulation of MML-1. In contrast, the Myc-Mondo complex is dispensable for the nuclear accumulation of DAF-16 by decreased ILS, and overexpression of DAF-16::GFP rescues the shortened lifespan of mxl-2 mutant animals, which suggests that DAF-16 and the Myc-Mondo complex may co-regulate transcription at overlapping target genes. From a candidate approach, we find that Myc-Mondo is required for the induction of longevity genes by decreased ILS. DAF-16, PHA-4, and MDL-1 bind within the genome at many overlapping target genes involved in unfolded protein binding, carbohydrate metabolism, autophagy, and stress response. Finally, loss of the Myc-Mondo complex impairs oxidative and thermal stress survival. Collectively, our results suggest that Myc family members are regulated by diverse signals of metabolic status and converge with DAF-16 and PHA-4 at metabolic and cytoprotective transcriptional programs that influence aging (Figure 8).


The Caenorhabditis elegans Myc-Mondo/Mad complexes integrate diverse longevity signals.

Johnson DW, Llop JR, Farrell SF, Yuan J, Stolzenburg LR, Samuelson AV - PLoS Genet. (2014)

Model for Myc-Mondo/Mad transcription factors in longevity control under basal conditions the Myc-Mondo activation complex (MML-1:MXL-2) is largely inactive, and transcription of genes encoding functions related to aging is limited by the Mad transcriptional repression complex (MDL-1:MXL-1).Conditions of reduced ILS and DR promote Myc-Mondo complex activity, likely by regulating cellular localization and transcription of mml-1. Myc-Mondo/Mad transcription factors may cooperate with DAF-16 and PHA-4 to modulate the expression of key metabolic and cytoprotective genes to influence aging.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3974684&req=5

pgen-1004278-g008: Model for Myc-Mondo/Mad transcription factors in longevity control under basal conditions the Myc-Mondo activation complex (MML-1:MXL-2) is largely inactive, and transcription of genes encoding functions related to aging is limited by the Mad transcriptional repression complex (MDL-1:MXL-1).Conditions of reduced ILS and DR promote Myc-Mondo complex activity, likely by regulating cellular localization and transcription of mml-1. Myc-Mondo/Mad transcription factors may cooperate with DAF-16 and PHA-4 to modulate the expression of key metabolic and cytoprotective genes to influence aging.
Mentions: The Myc family of transcription factors have well established functions in growth control and metabolic regulation; processes that are known to influence lifespan. Yet, this is the first study to identify a role for the Myc interaction network in longevity control and proteostasis. We have identified a role for the Myc-family of bHLH transcription factors: mml-1, mdl-1, mxl-1, and mxl-2 in the regulation of C. elegans lifespan. We show that the Myc-Mondo (MML-1:MXL-2) and Mad (MDL-1:MXL-1) transcriptional complexes have opposing roles in longevity control and proteostasis analogous to their known functions as transcriptional activators and repressors in C. elegans[11]. Specifically, loss of the Myc-Mondo complex leads to premature aging, while loss of the Mad complex delays aging. Lifespan extension by loss of the Mad complex is dependent upon the Myc-Mondo complex, daf-16, and pha-4, suggesting a common mechanism in longevity control. Conversely, Myc-Mondo is required for lifespan extension by decreased ILS or conditions of DR. Both decreased ILS and conditions of DR promote nuclear accumulation of MML-1, but do so through distinct mechanisms; altered DAF-16 activity regulates expression of Myc family members, while pha-4 is essential for the increased nuclear accumulation of MML-1. In contrast, the Myc-Mondo complex is dispensable for the nuclear accumulation of DAF-16 by decreased ILS, and overexpression of DAF-16::GFP rescues the shortened lifespan of mxl-2 mutant animals, which suggests that DAF-16 and the Myc-Mondo complex may co-regulate transcription at overlapping target genes. From a candidate approach, we find that Myc-Mondo is required for the induction of longevity genes by decreased ILS. DAF-16, PHA-4, and MDL-1 bind within the genome at many overlapping target genes involved in unfolded protein binding, carbohydrate metabolism, autophagy, and stress response. Finally, loss of the Myc-Mondo complex impairs oxidative and thermal stress survival. Collectively, our results suggest that Myc family members are regulated by diverse signals of metabolic status and converge with DAF-16 and PHA-4 at metabolic and cytoprotective transcriptional programs that influence aging (Figure 8).

Bottom Line: Furthermore, decreased insulin-like/IGF-1 signaling (ILS) or conditions of dietary restriction increase the accumulation of MML-1, consistent with the notion that the Myc family members function as sensors of metabolic status.We compared putative target genes based on ChIP-sequencing data in the modENCODE project and found significant overlap in genomic DNA binding between the major effectors of ILS (DAF-16/FoxO), DR (PHA-4/FoxA), and Myc family (MDL-1/Mad/Mxd) at common target genes, which suggests that diverse signals of metabolic status converge on overlapping transcriptional programs that influence aging.Additionally, we find that Myc family members are also involved in stress response and the maintenance of protein homeostasis.

View Article: PubMed Central - PubMed

Affiliation: University of Rochester, Department of Biomedical Genetics, Rochester, New York, United States of America.

ABSTRACT
The Myc family of transcription factors regulates a variety of biological processes, including the cell cycle, growth, proliferation, metabolism, and apoptosis. In Caenorhabditis elegans, the "Myc interaction network" consists of two opposing heterodimeric complexes with antagonistic functions in transcriptional control: the Myc-Mondo:Mlx transcriptional activation complex and the Mad:Max transcriptional repression complex. In C. elegans, Mondo, Mlx, Mad, and Max are encoded by mml-1, mxl-2, mdl-1, and mxl-1, respectively. Here we show a similar antagonistic role for the C. elegans Myc-Mondo and Mad complexes in longevity control. Loss of mml-1 or mxl-2 shortens C. elegans lifespan. In contrast, loss of mdl-1 or mxl-1 increases longevity, dependent upon MML-1:MXL-2. The MML-1:MXL-2 and MDL-1:MXL-1 complexes function in both the insulin signaling and dietary restriction pathways. Furthermore, decreased insulin-like/IGF-1 signaling (ILS) or conditions of dietary restriction increase the accumulation of MML-1, consistent with the notion that the Myc family members function as sensors of metabolic status. Additionally, we find that Myc family members are regulated by distinct mechanisms, which would allow for integrated control of gene expression from diverse signals of metabolic status. We compared putative target genes based on ChIP-sequencing data in the modENCODE project and found significant overlap in genomic DNA binding between the major effectors of ILS (DAF-16/FoxO), DR (PHA-4/FoxA), and Myc family (MDL-1/Mad/Mxd) at common target genes, which suggests that diverse signals of metabolic status converge on overlapping transcriptional programs that influence aging. Consistent with this, there is over-enrichment at these common targets for genes that function in lifespan, stress response, and carbohydrate metabolism. Additionally, we find that Myc family members are also involved in stress response and the maintenance of protein homeostasis. Collectively, these findings indicate that Myc family members integrate diverse signals of metabolic status, to coordinate overlapping metabolic and cytoprotective transcriptional programs that determine the progression of aging.

Show MeSH
Related in: MedlinePlus