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

The Myc-Mondo/Mad complexes intersect with dietary restriction in longevity.(A) RNAi inactivation of pha-4 ablates the lifespan extension conferred by the mxl-1(tm1530)  mutation (light blue versus blue traces), and does not further shorten the lifespan of mxl-2(tm1516)  mutant animals (pink versus red traces). (B) RNAi inactivation of mxl-2 partially suppresses the extended lifespan observed in eat-2(ad465) mutants (pink versus green traces). Similar results were obtained with mml-1 RNAi (Dataset S1). (C) The mxl-2(tm1516)  mutation partially suppresses the extended lifespan observed in eat-2(ad465) mutant animals (pink versus green traces). (D) The mxl-1(tm1530)  mutation does not further extend the lifespan of eat-2(ad465) mutant animals (dark blue versus green traces). Similar results were obtained with mxl-1 and mdl-1 RNAi (Dataset S1). Traces represent the combined data from multiple separate trials. Complete information regarding the number of trials, total number of animals examined, and statistical significance for each experiment can be found in Dataset S1. Experiments shown within this figure were performed simultaneously with those shown in Figure 2 and were split into multiple figures for readability.
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1004278-g003: The Myc-Mondo/Mad complexes intersect with dietary restriction in longevity.(A) RNAi inactivation of pha-4 ablates the lifespan extension conferred by the mxl-1(tm1530) mutation (light blue versus blue traces), and does not further shorten the lifespan of mxl-2(tm1516) mutant animals (pink versus red traces). (B) RNAi inactivation of mxl-2 partially suppresses the extended lifespan observed in eat-2(ad465) mutants (pink versus green traces). Similar results were obtained with mml-1 RNAi (Dataset S1). (C) The mxl-2(tm1516) mutation partially suppresses the extended lifespan observed in eat-2(ad465) mutant animals (pink versus green traces). (D) The mxl-1(tm1530) mutation does not further extend the lifespan of eat-2(ad465) mutant animals (dark blue versus green traces). Similar results were obtained with mxl-1 and mdl-1 RNAi (Dataset S1). Traces represent the combined data from multiple separate trials. Complete information regarding the number of trials, total number of animals examined, and statistical significance for each experiment can be found in Dataset S1. Experiments shown within this figure were performed simultaneously with those shown in Figure 2 and were split into multiple figures for readability.

Mentions: (A) RNAi inactivation of daf-16 ablates the lifespan extension conferred by mxl-1(tm1530) mutation (dark blue versus blue traces), and does not further shorten the lifespan of mxl-2(tm1516) mutants (pink versus red traces). Reciprocal experiments show that RNAi inactivation of mxl-1 or mdl-1 do not extend the lifespan of daf-16(mgDf47) mutant animals, nor does RNAi inactivation of mxl-2 or mml-1 further shorten the lifespan of daf-16(mgDf47) mutant animals (Dataset S1). (B) RNAi inactivation of mxl-2 partially suppresses the lifespan of daf-2(e1370) mutant animals (pink versus gray traces). Similar results were obtained with mml-1 RNAi (Figure S2A). (C) The mxl-2(tm1516) mutation partially suppresses the extended lifespan observed in daf-2(e1370) mutant animals (pink versus gray traces). (D) RNAi inactivation of daf-2 does not further extend the lifespan of mxl-1(tm1530); daf-2(e1370) mutant animals (darker blue versus light blue traces). Traces represent the combined data from multiple separate trials. Complete information regarding the number of trials, total number of animals examined, and statistical significance for each experiment can be found in Dataset S1. Experiments shown within this figure were performed simultaneously with those shown in Figure 3 and were split into multiple figures for readability.


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)

The Myc-Mondo/Mad complexes intersect with dietary restriction in longevity.(A) RNAi inactivation of pha-4 ablates the lifespan extension conferred by the mxl-1(tm1530)  mutation (light blue versus blue traces), and does not further shorten the lifespan of mxl-2(tm1516)  mutant animals (pink versus red traces). (B) RNAi inactivation of mxl-2 partially suppresses the extended lifespan observed in eat-2(ad465) mutants (pink versus green traces). Similar results were obtained with mml-1 RNAi (Dataset S1). (C) The mxl-2(tm1516)  mutation partially suppresses the extended lifespan observed in eat-2(ad465) mutant animals (pink versus green traces). (D) The mxl-1(tm1530)  mutation does not further extend the lifespan of eat-2(ad465) mutant animals (dark blue versus green traces). Similar results were obtained with mxl-1 and mdl-1 RNAi (Dataset S1). Traces represent the combined data from multiple separate trials. Complete information regarding the number of trials, total number of animals examined, and statistical significance for each experiment can be found in Dataset S1. Experiments shown within this figure were performed simultaneously with those shown in Figure 2 and were split into multiple figures for readability.
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1004278-g003: The Myc-Mondo/Mad complexes intersect with dietary restriction in longevity.(A) RNAi inactivation of pha-4 ablates the lifespan extension conferred by the mxl-1(tm1530) mutation (light blue versus blue traces), and does not further shorten the lifespan of mxl-2(tm1516) mutant animals (pink versus red traces). (B) RNAi inactivation of mxl-2 partially suppresses the extended lifespan observed in eat-2(ad465) mutants (pink versus green traces). Similar results were obtained with mml-1 RNAi (Dataset S1). (C) The mxl-2(tm1516) mutation partially suppresses the extended lifespan observed in eat-2(ad465) mutant animals (pink versus green traces). (D) The mxl-1(tm1530) mutation does not further extend the lifespan of eat-2(ad465) mutant animals (dark blue versus green traces). Similar results were obtained with mxl-1 and mdl-1 RNAi (Dataset S1). Traces represent the combined data from multiple separate trials. Complete information regarding the number of trials, total number of animals examined, and statistical significance for each experiment can be found in Dataset S1. Experiments shown within this figure were performed simultaneously with those shown in Figure 2 and were split into multiple figures for readability.
Mentions: (A) RNAi inactivation of daf-16 ablates the lifespan extension conferred by mxl-1(tm1530) mutation (dark blue versus blue traces), and does not further shorten the lifespan of mxl-2(tm1516) mutants (pink versus red traces). Reciprocal experiments show that RNAi inactivation of mxl-1 or mdl-1 do not extend the lifespan of daf-16(mgDf47) mutant animals, nor does RNAi inactivation of mxl-2 or mml-1 further shorten the lifespan of daf-16(mgDf47) mutant animals (Dataset S1). (B) RNAi inactivation of mxl-2 partially suppresses the lifespan of daf-2(e1370) mutant animals (pink versus gray traces). Similar results were obtained with mml-1 RNAi (Figure S2A). (C) The mxl-2(tm1516) mutation partially suppresses the extended lifespan observed in daf-2(e1370) mutant animals (pink versus gray traces). (D) RNAi inactivation of daf-2 does not further extend the lifespan of mxl-1(tm1530); daf-2(e1370) mutant animals (darker blue versus light blue traces). Traces represent the combined data from multiple separate trials. Complete information regarding the number of trials, total number of animals examined, and statistical significance for each experiment can be found in Dataset S1. Experiments shown within this figure were performed simultaneously with those shown in Figure 3 and were split into multiple figures for readability.

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