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Lipid-mediated regulation of SKN-1/Nrf in response to germ cell absence.

Steinbaugh MJ, Narasimhan SD, Robida-Stubbs S, Moronetti Mazzeo LE, Dreyfuss JM, Hourihan JM, Raghavan P, Operaña TN, Esmaillie R, Blackwell TK - Elife (2015)

Bottom Line: Surprisingly, SKN-1 is activated by signals from this fat, which appears to derive from unconsumed yolk that was produced for reproduction.We conclude that SKN-1 plays a direct role in maintaining lipid homeostasis in which it is activated by lipids.This SKN-1 function may explain the importance of mammalian Nrf proteins in fatty liver disease and suggest that particular endogenous or dietary lipids might promote health through SKN-1/Nrf.

View Article: PubMed Central - PubMed

Affiliation: Research Division, Joslin Diabetes Center, Boston, United States.

ABSTRACT
In Caenorhabditis elegans, ablation of germline stem cells (GSCs) extends lifespan, but also increases fat accumulation and alters lipid metabolism, raising the intriguing question of how these effects might be related. Here, we show that a lack of GSCs results in a broad transcriptional reprogramming in which the conserved detoxification regulator SKN-1/Nrf increases stress resistance, proteasome activity, and longevity. SKN-1 also activates diverse lipid metabolism genes and reduces fat storage, thereby alleviating the increased fat accumulation caused by GSC absence. Surprisingly, SKN-1 is activated by signals from this fat, which appears to derive from unconsumed yolk that was produced for reproduction. We conclude that SKN-1 plays a direct role in maintaining lipid homeostasis in which it is activated by lipids. This SKN-1 function may explain the importance of mammalian Nrf proteins in fatty liver disease and suggest that particular endogenous or dietary lipids might promote health through SKN-1/Nrf.

No MeSH data available.


Related in: MedlinePlus

Gene expression changes following GSC inhibition.(A) qRT-PCR validation of RNA samples used for RNA-seq. gst-4 and nit-1 are direct SKN-1 targets (Robida-Stubbs et al., 2012). Data are represented as mean ± SEM. n = 3; p < 0.05*. Analysis of a different RNA sample set is shown in Figure 2D. (B) DAVID analysis of genes that were downregulated in glp-1(ts). Processes related to GSC maintenance and reproduction were highly represented, as expected. (C) Altered abundance of tissue-specific genes in GSC(−) animals. Adult hermaphrodite worms have 959 somatic cells and ∼2000 GSCs (Kimble and Crittenden, 2005). A representative somatic-specific gene would therefore be predicted to be present at higher relative abundance in GSC(−) samples after normalization to either total RNA or reference housekeeping genes. Accordingly, representative somatic tissue-specific genes (Richmond, 2005; Moerman and Williams, 2006; Chikina et al., 2009) were present at threefold to fourfold higher relative levels in the GSC(−) samples. By contrast, a germline-specific gene (efl-1) was underrepresented (∼4×) in GSC(−) samples. Reference genes that are ubiquitously expressed in all tissues and commonly used for qRT-PCR normalization (Hoogewijs et al., 2008) do not have altered relative abundance in the GSC(−) samples. (D, E) Frequency distribution plots of mRNA levels in glp-1(ts) worms relative to wild type. A cutoff of FC > 4 denotes 1,306 out of 12,595 genes sequenced (10.4%).DOI:http://dx.doi.org/10.7554/eLife.07836.008
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fig3s1: Gene expression changes following GSC inhibition.(A) qRT-PCR validation of RNA samples used for RNA-seq. gst-4 and nit-1 are direct SKN-1 targets (Robida-Stubbs et al., 2012). Data are represented as mean ± SEM. n = 3; p < 0.05*. Analysis of a different RNA sample set is shown in Figure 2D. (B) DAVID analysis of genes that were downregulated in glp-1(ts). Processes related to GSC maintenance and reproduction were highly represented, as expected. (C) Altered abundance of tissue-specific genes in GSC(−) animals. Adult hermaphrodite worms have 959 somatic cells and ∼2000 GSCs (Kimble and Crittenden, 2005). A representative somatic-specific gene would therefore be predicted to be present at higher relative abundance in GSC(−) samples after normalization to either total RNA or reference housekeeping genes. Accordingly, representative somatic tissue-specific genes (Richmond, 2005; Moerman and Williams, 2006; Chikina et al., 2009) were present at threefold to fourfold higher relative levels in the GSC(−) samples. By contrast, a germline-specific gene (efl-1) was underrepresented (∼4×) in GSC(−) samples. Reference genes that are ubiquitously expressed in all tissues and commonly used for qRT-PCR normalization (Hoogewijs et al., 2008) do not have altered relative abundance in the GSC(−) samples. (D, E) Frequency distribution plots of mRNA levels in glp-1(ts) worms relative to wild type. A cutoff of FC > 4 denotes 1,306 out of 12,595 genes sequenced (10.4%).DOI:http://dx.doi.org/10.7554/eLife.07836.008

Mentions: To investigate how SKN-1 promotes longevity and stress resistance upon GSC loss, we used RNA sequencing (RNA-seq) to identify genes that are (1) expressed at higher levels in adult somatic tissues when germ cells are largely absent and (2) dependent upon SKN-1 (Figure 3A). We compared intact glp-1(ts) (GSC(−)) animals to wild-type GSC(+) controls at the non-permissive temperature of 25°, analyzing day-1 adults in which development was complete and performing differential expression analyses on the normalized RNA-seq data for 12,595 expressed genes (Figure 3B). We detected similar expression levels of SKN-1 upregulated targets in qRT-PCR analyses of the samples used for sequencing, giving us confidence in our RNA-seq results (Figure 3—figure supplement 1A). Moreover, in the GSC(−) gene set, the canonical DAF-16 targets mtl-1 and sod-3 (Murphy et al., 2003; Kenyon, 2010) were upregulated (Supplementary file 1a), and functional groups that are characteristic of germline-specific genes were under-represented (Figure 3—figure supplement 1B).10.7554/eLife.07836.007Figure 3.Effects of GSC absence and skn-1 on gene expression.


Lipid-mediated regulation of SKN-1/Nrf in response to germ cell absence.

Steinbaugh MJ, Narasimhan SD, Robida-Stubbs S, Moronetti Mazzeo LE, Dreyfuss JM, Hourihan JM, Raghavan P, Operaña TN, Esmaillie R, Blackwell TK - Elife (2015)

Gene expression changes following GSC inhibition.(A) qRT-PCR validation of RNA samples used for RNA-seq. gst-4 and nit-1 are direct SKN-1 targets (Robida-Stubbs et al., 2012). Data are represented as mean ± SEM. n = 3; p < 0.05*. Analysis of a different RNA sample set is shown in Figure 2D. (B) DAVID analysis of genes that were downregulated in glp-1(ts). Processes related to GSC maintenance and reproduction were highly represented, as expected. (C) Altered abundance of tissue-specific genes in GSC(−) animals. Adult hermaphrodite worms have 959 somatic cells and ∼2000 GSCs (Kimble and Crittenden, 2005). A representative somatic-specific gene would therefore be predicted to be present at higher relative abundance in GSC(−) samples after normalization to either total RNA or reference housekeeping genes. Accordingly, representative somatic tissue-specific genes (Richmond, 2005; Moerman and Williams, 2006; Chikina et al., 2009) were present at threefold to fourfold higher relative levels in the GSC(−) samples. By contrast, a germline-specific gene (efl-1) was underrepresented (∼4×) in GSC(−) samples. Reference genes that are ubiquitously expressed in all tissues and commonly used for qRT-PCR normalization (Hoogewijs et al., 2008) do not have altered relative abundance in the GSC(−) samples. (D, E) Frequency distribution plots of mRNA levels in glp-1(ts) worms relative to wild type. A cutoff of FC > 4 denotes 1,306 out of 12,595 genes sequenced (10.4%).DOI:http://dx.doi.org/10.7554/eLife.07836.008
© Copyright Policy
Related In: Results  -  Collection

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fig3s1: Gene expression changes following GSC inhibition.(A) qRT-PCR validation of RNA samples used for RNA-seq. gst-4 and nit-1 are direct SKN-1 targets (Robida-Stubbs et al., 2012). Data are represented as mean ± SEM. n = 3; p < 0.05*. Analysis of a different RNA sample set is shown in Figure 2D. (B) DAVID analysis of genes that were downregulated in glp-1(ts). Processes related to GSC maintenance and reproduction were highly represented, as expected. (C) Altered abundance of tissue-specific genes in GSC(−) animals. Adult hermaphrodite worms have 959 somatic cells and ∼2000 GSCs (Kimble and Crittenden, 2005). A representative somatic-specific gene would therefore be predicted to be present at higher relative abundance in GSC(−) samples after normalization to either total RNA or reference housekeeping genes. Accordingly, representative somatic tissue-specific genes (Richmond, 2005; Moerman and Williams, 2006; Chikina et al., 2009) were present at threefold to fourfold higher relative levels in the GSC(−) samples. By contrast, a germline-specific gene (efl-1) was underrepresented (∼4×) in GSC(−) samples. Reference genes that are ubiquitously expressed in all tissues and commonly used for qRT-PCR normalization (Hoogewijs et al., 2008) do not have altered relative abundance in the GSC(−) samples. (D, E) Frequency distribution plots of mRNA levels in glp-1(ts) worms relative to wild type. A cutoff of FC > 4 denotes 1,306 out of 12,595 genes sequenced (10.4%).DOI:http://dx.doi.org/10.7554/eLife.07836.008
Mentions: To investigate how SKN-1 promotes longevity and stress resistance upon GSC loss, we used RNA sequencing (RNA-seq) to identify genes that are (1) expressed at higher levels in adult somatic tissues when germ cells are largely absent and (2) dependent upon SKN-1 (Figure 3A). We compared intact glp-1(ts) (GSC(−)) animals to wild-type GSC(+) controls at the non-permissive temperature of 25°, analyzing day-1 adults in which development was complete and performing differential expression analyses on the normalized RNA-seq data for 12,595 expressed genes (Figure 3B). We detected similar expression levels of SKN-1 upregulated targets in qRT-PCR analyses of the samples used for sequencing, giving us confidence in our RNA-seq results (Figure 3—figure supplement 1A). Moreover, in the GSC(−) gene set, the canonical DAF-16 targets mtl-1 and sod-3 (Murphy et al., 2003; Kenyon, 2010) were upregulated (Supplementary file 1a), and functional groups that are characteristic of germline-specific genes were under-represented (Figure 3—figure supplement 1B).10.7554/eLife.07836.007Figure 3.Effects of GSC absence and skn-1 on gene expression.

Bottom Line: Surprisingly, SKN-1 is activated by signals from this fat, which appears to derive from unconsumed yolk that was produced for reproduction.We conclude that SKN-1 plays a direct role in maintaining lipid homeostasis in which it is activated by lipids.This SKN-1 function may explain the importance of mammalian Nrf proteins in fatty liver disease and suggest that particular endogenous or dietary lipids might promote health through SKN-1/Nrf.

View Article: PubMed Central - PubMed

Affiliation: Research Division, Joslin Diabetes Center, Boston, United States.

ABSTRACT
In Caenorhabditis elegans, ablation of germline stem cells (GSCs) extends lifespan, but also increases fat accumulation and alters lipid metabolism, raising the intriguing question of how these effects might be related. Here, we show that a lack of GSCs results in a broad transcriptional reprogramming in which the conserved detoxification regulator SKN-1/Nrf increases stress resistance, proteasome activity, and longevity. SKN-1 also activates diverse lipid metabolism genes and reduces fat storage, thereby alleviating the increased fat accumulation caused by GSC absence. Surprisingly, SKN-1 is activated by signals from this fat, which appears to derive from unconsumed yolk that was produced for reproduction. We conclude that SKN-1 plays a direct role in maintaining lipid homeostasis in which it is activated by lipids. This SKN-1 function may explain the importance of mammalian Nrf proteins in fatty liver disease and suggest that particular endogenous or dietary lipids might promote health through SKN-1/Nrf.

No MeSH data available.


Related in: MedlinePlus