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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.

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ChIP-seq data shows significant overlap amongst MDL-1, DAF-16, and PHA-4 promoter binding.(A) Analysis of binding sites throughout the genome indicates that MDL-1 (blue) and PHA-4 (red) bind predominantly in a region located –700 to +100 bp (dashed lines) relative to the transcriptional start site (TSS). (B) Venn diagram based on ChIP-Seq data showing gene promoters bound by MDL-1, DAF-16, and PHA-4. Numbers indicate the total number of genes belonging to each group. Parenthesis denote the number of genes belonging to each group that have previously been annotated to be involved in aging (based on published studies, gene ontology and description). The inset box shows the total number of genes in the genome that are not bound by MDL-1, DAF-16, and PHA-4. (C) GO terms related to aging that are enriched in genes bound by MDL-1, DAF-16, and PHA-4 versus the entire genome (p <0.05). The total number of common target genes annotated with each GO term is shown to the right of each bar. Enrichment was determined as described in Materials and Methods. Details of this analysis can be found in Dataset S2 (D) Analysis of metabolic pathways contained within the GO term “carbohydrate metabolic process” (GO: 0005975). The total number of genes annotated within each pathway is shown. Some genes belong to more than one category, notably several genes function in glycolysis and gluconeogenesis. Details can be found in Dataset S2 (E) An analysis of stress response pathways contained with the GO term “response to stress” (GO: 0006950). The total number of genes annotated to be involved in each pathway is shown. Many genes are important for resistance to multiple stresses. Details can be found in Dataset S2. (F) qRT-PCR analysis of Class I genes [37] known to be bound by MDL-1, DAF-16, and PHA-4 in daf-2(e1370), daf-2(e1370);daf-16(mgDf47), and daf-2(e1370);mxl-2(tm1516) animals. Class I genes were significantly upregulated (* denotes p<0.01) in daf-2(e1370) in a daf-16 dependent manner as previously described [13], [37]. Additionally, icl-1, hsp-12.6, and stdh-1 failed to be induced in daf-2(e1370);mxl-2(tm1516) mutants as well.
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pgen-1004278-g005: ChIP-seq data shows significant overlap amongst MDL-1, DAF-16, and PHA-4 promoter binding.(A) Analysis of binding sites throughout the genome indicates that MDL-1 (blue) and PHA-4 (red) bind predominantly in a region located –700 to +100 bp (dashed lines) relative to the transcriptional start site (TSS). (B) Venn diagram based on ChIP-Seq data showing gene promoters bound by MDL-1, DAF-16, and PHA-4. Numbers indicate the total number of genes belonging to each group. Parenthesis denote the number of genes belonging to each group that have previously been annotated to be involved in aging (based on published studies, gene ontology and description). The inset box shows the total number of genes in the genome that are not bound by MDL-1, DAF-16, and PHA-4. (C) GO terms related to aging that are enriched in genes bound by MDL-1, DAF-16, and PHA-4 versus the entire genome (p <0.05). The total number of common target genes annotated with each GO term is shown to the right of each bar. Enrichment was determined as described in Materials and Methods. Details of this analysis can be found in Dataset S2 (D) Analysis of metabolic pathways contained within the GO term “carbohydrate metabolic process” (GO: 0005975). The total number of genes annotated within each pathway is shown. Some genes belong to more than one category, notably several genes function in glycolysis and gluconeogenesis. Details can be found in Dataset S2 (E) An analysis of stress response pathways contained with the GO term “response to stress” (GO: 0006950). The total number of genes annotated to be involved in each pathway is shown. Many genes are important for resistance to multiple stresses. Details can be found in Dataset S2. (F) qRT-PCR analysis of Class I genes [37] known to be bound by MDL-1, DAF-16, and PHA-4 in daf-2(e1370), daf-2(e1370);daf-16(mgDf47), and daf-2(e1370);mxl-2(tm1516) animals. Class I genes were significantly upregulated (* denotes p<0.01) in daf-2(e1370) in a daf-16 dependent manner as previously described [13], [37]. Additionally, icl-1, hsp-12.6, and stdh-1 failed to be induced in daf-2(e1370);mxl-2(tm1516) mutants as well.

Mentions: We found that the Myc family members are regulated by DR and ILS signaling and have overlapping functions in longevity control, implying that the C. elegans Myc-Mondo/Mad complexes may cooperate with PHA-4 and DAF-16 at shared target gene promoters. Through an informatics analysis of available ChIP-seq data provided by the modENCODE project (www.modENCODE.org) [38], we sought to identify the overlap in genomic binding sites for DAF-16, PHA-4, and MDL-1. We compared the global frequency of the MDL-1 and PHA-4 binding midpoints to the position of the transcription start site (TSS), as has been done for DAF-16 [37]. MDL-1 and PHA-4 had enriched binding frequency within a region almost identical to what has been reported for DAF-16 (between –700 to +100 of the TSS, Figure 5A). We used this metric to distinguish genes more likely to be regulated by MDL-1, and identified 4605 possible target genes. The Myc family of bHLH transcription factors bind to E box sequences, therefore we asked whether the MDL-1 binding regions identified by ChIP-seq also contained E boxes, and found this to be true in 3555 cases (77.2%, Dataset S2). Next, we found that there is significant overlap of 2879 target genes that are bound by DAF-16, PHA-4, and MDL-1 (Figure 5B, p = 2.2e−16). Of 963 genes that have been identified as influencing longevity (based on published studies, gene ontology and description), 299 are bound by DAF-16, PHA-4, and MDL-1. In contrast, only 13 previously identified longevity genes are bound by MDL-1 and not DAF-16 or PHA-4, a significant enrichment (p = 2.2e−16). We next asked whether the actual binding sites of the three transcription factors overlapped. For 234 of 299 putative longevity genes the MDL-1 binding peak is 75% or more overlapped by DAF-16 and PHA-4, suggesting that binding occurs in common regulatory regions. We conclude that DAF-16, PHA-4, and MDL-1 bind at many common target genes, in common regions.


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)

ChIP-seq data shows significant overlap amongst MDL-1, DAF-16, and PHA-4 promoter binding.(A) Analysis of binding sites throughout the genome indicates that MDL-1 (blue) and PHA-4 (red) bind predominantly in a region located –700 to +100 bp (dashed lines) relative to the transcriptional start site (TSS). (B) Venn diagram based on ChIP-Seq data showing gene promoters bound by MDL-1, DAF-16, and PHA-4. Numbers indicate the total number of genes belonging to each group. Parenthesis denote the number of genes belonging to each group that have previously been annotated to be involved in aging (based on published studies, gene ontology and description). The inset box shows the total number of genes in the genome that are not bound by MDL-1, DAF-16, and PHA-4. (C) GO terms related to aging that are enriched in genes bound by MDL-1, DAF-16, and PHA-4 versus the entire genome (p <0.05). The total number of common target genes annotated with each GO term is shown to the right of each bar. Enrichment was determined as described in Materials and Methods. Details of this analysis can be found in Dataset S2 (D) Analysis of metabolic pathways contained within the GO term “carbohydrate metabolic process” (GO: 0005975). The total number of genes annotated within each pathway is shown. Some genes belong to more than one category, notably several genes function in glycolysis and gluconeogenesis. Details can be found in Dataset S2 (E) An analysis of stress response pathways contained with the GO term “response to stress” (GO: 0006950). The total number of genes annotated to be involved in each pathway is shown. Many genes are important for resistance to multiple stresses. Details can be found in Dataset S2. (F) qRT-PCR analysis of Class I genes [37] known to be bound by MDL-1, DAF-16, and PHA-4 in daf-2(e1370), daf-2(e1370);daf-16(mgDf47), and daf-2(e1370);mxl-2(tm1516) animals. Class I genes were significantly upregulated (* denotes p<0.01) in daf-2(e1370) in a daf-16 dependent manner as previously described [13], [37]. Additionally, icl-1, hsp-12.6, and stdh-1 failed to be induced in daf-2(e1370);mxl-2(tm1516) mutants as well.
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Show All Figures
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pgen-1004278-g005: ChIP-seq data shows significant overlap amongst MDL-1, DAF-16, and PHA-4 promoter binding.(A) Analysis of binding sites throughout the genome indicates that MDL-1 (blue) and PHA-4 (red) bind predominantly in a region located –700 to +100 bp (dashed lines) relative to the transcriptional start site (TSS). (B) Venn diagram based on ChIP-Seq data showing gene promoters bound by MDL-1, DAF-16, and PHA-4. Numbers indicate the total number of genes belonging to each group. Parenthesis denote the number of genes belonging to each group that have previously been annotated to be involved in aging (based on published studies, gene ontology and description). The inset box shows the total number of genes in the genome that are not bound by MDL-1, DAF-16, and PHA-4. (C) GO terms related to aging that are enriched in genes bound by MDL-1, DAF-16, and PHA-4 versus the entire genome (p <0.05). The total number of common target genes annotated with each GO term is shown to the right of each bar. Enrichment was determined as described in Materials and Methods. Details of this analysis can be found in Dataset S2 (D) Analysis of metabolic pathways contained within the GO term “carbohydrate metabolic process” (GO: 0005975). The total number of genes annotated within each pathway is shown. Some genes belong to more than one category, notably several genes function in glycolysis and gluconeogenesis. Details can be found in Dataset S2 (E) An analysis of stress response pathways contained with the GO term “response to stress” (GO: 0006950). The total number of genes annotated to be involved in each pathway is shown. Many genes are important for resistance to multiple stresses. Details can be found in Dataset S2. (F) qRT-PCR analysis of Class I genes [37] known to be bound by MDL-1, DAF-16, and PHA-4 in daf-2(e1370), daf-2(e1370);daf-16(mgDf47), and daf-2(e1370);mxl-2(tm1516) animals. Class I genes were significantly upregulated (* denotes p<0.01) in daf-2(e1370) in a daf-16 dependent manner as previously described [13], [37]. Additionally, icl-1, hsp-12.6, and stdh-1 failed to be induced in daf-2(e1370);mxl-2(tm1516) mutants as well.
Mentions: We found that the Myc family members are regulated by DR and ILS signaling and have overlapping functions in longevity control, implying that the C. elegans Myc-Mondo/Mad complexes may cooperate with PHA-4 and DAF-16 at shared target gene promoters. Through an informatics analysis of available ChIP-seq data provided by the modENCODE project (www.modENCODE.org) [38], we sought to identify the overlap in genomic binding sites for DAF-16, PHA-4, and MDL-1. We compared the global frequency of the MDL-1 and PHA-4 binding midpoints to the position of the transcription start site (TSS), as has been done for DAF-16 [37]. MDL-1 and PHA-4 had enriched binding frequency within a region almost identical to what has been reported for DAF-16 (between –700 to +100 of the TSS, Figure 5A). We used this metric to distinguish genes more likely to be regulated by MDL-1, and identified 4605 possible target genes. The Myc family of bHLH transcription factors bind to E box sequences, therefore we asked whether the MDL-1 binding regions identified by ChIP-seq also contained E boxes, and found this to be true in 3555 cases (77.2%, Dataset S2). Next, we found that there is significant overlap of 2879 target genes that are bound by DAF-16, PHA-4, and MDL-1 (Figure 5B, p = 2.2e−16). Of 963 genes that have been identified as influencing longevity (based on published studies, gene ontology and description), 299 are bound by DAF-16, PHA-4, and MDL-1. In contrast, only 13 previously identified longevity genes are bound by MDL-1 and not DAF-16 or PHA-4, a significant enrichment (p = 2.2e−16). We next asked whether the actual binding sites of the three transcription factors overlapped. For 234 of 299 putative longevity genes the MDL-1 binding peak is 75% or more overlapped by DAF-16 and PHA-4, suggesting that binding occurs in common regulatory regions. We conclude that DAF-16, PHA-4, and MDL-1 bind at many common target genes, in common regions.

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