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Ubiquitylome study identifies increased histone 2A ubiquitylation as an evolutionarily conserved aging biomarker

Yang, Lu, Ma, Zaijun, Wang, Han, Niu, Kongyan, Cao, Ye, Sun, Le, Geng, Yang, Yang, Bo, Gao, Feng, Chen, Zuolong, Wu, Zhen, Li, Qingqing, Shen, Yong, Zhang, Xumin, Jiang, Hong, Chen, Yelin, Liu, Rui, Liu, Nan, Zhang, Yaoyang·2019·Nature Communications
DOI 10.1038/s41467-019-10136-wPMC PMC6529468
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Abstract

The long-lived proteome constitutes a pool of exceptionally stable proteins with limited turnover. Previous studies on ubiquitin-mediated protein degradation primarily focused on relatively short-lived proteins; how ubiquitylation modifies the long-lived proteome and its regulatory effect on adult lifespan is unclear. Here we profile the age-dependent dynamics of long-lived proteomes in Drosophila by mass spectrometry using stable isotope switching coupled with antibody-enriched ubiquitylome analysis. Our data describe landscapes of long-lived proteins in somatic and reproductive tissues of Drosophila during adult lifespan, and reveal a preferential ubiquitylation of older long-lived proteins. We identify an age-modulated increase of ubiquitylation on long-lived histone 2A protein in Drosophila , which is evolutionarily conserved in mouse, monkey, and human. A reduction of ubiquitylated histone 2A in mutant flies is associated with longevity and healthy lifespan. Together, our data reveal an evolutionarily conserved biomarker of aging that links epigenetic modulation of the long-lived histone protein to lifespan.

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Fig. 1 Long-lived proteome analysis during Drosophila aging. a Experimental scheme of metabolic labeling in Drosophila. Flies were first fully labeled with 15N, and then switched to normal 14N food at 5d. Samples were collected at 5d, 30d, and 60d of age. Proteomes of three tissues with indicated ages, and the ubiquitylome of 60d old head and muscle tissues were analyzed. The proportion of 15N signal represents protein turnover rate. b 15N proportions (15N %) for each protein in different tissues and different aging time point. Proteins quantified during aging were compared across tissue types. A high 15N % value at aging time point represents a slow turnover rate. The protein identifiers were used for comparison among multiple datasets in this study. c Clustering of proteins according to their 15N proportion changes during aging. Proteins in cluster 1 were characterized with the slowest turnover rates thus defined as extremely long-lived proteins (ELLPs). The median values are marked at the center. The boxes extend from the 25th to 75th percentiles. The upper or lower whiskers extend from the hinge to the largest or smallest value no further than 1.5 times the interquartile range (IQR).d Venn diagram and GO analysis of ELLPs in head and muscle. 149 ELLPs were found in both head and muscle, two post-mitotic tissues, and then subjected to functional analysis, with “nucleosome assembly” as the most significant hit (p = 5.2e-9, Fisher’s exact test). e H2A and H2B are ELLPs. H2A and H2B belonging to “nucleosome assembly” category were identified with a dramatic enrichment of 15N signals at day 60. The extracted ion chromatographs (XICs) of the paired 15N and 14N peaks from two representative peptides were compared
Fig. 1 Long-lived proteome analysis during Drosophila aging. a Experimental scheme of metabolic labeling in Drosophila. Flies were first fully labeled with 15N, and then switched to normal 14N food at 5d. Samples were collected at 5d, 30d, and 60d of age. Proteomes of three tissues with indicated ages, and the ubiquitylome of 60d old head and muscle tissues were analyzed. The proportion of 15N signal represents protein turnover rate. b 15N proportions (15N %) for each protein in different tissues and different aging time point. Proteins quantified during aging were compared across tissue types. A high 15N % value at aging time point represents a slow turnover rate. The protein identifiers were used for comparison among multiple datasets in this study. c Clustering of proteins according to their 15N proportion changes during aging. Proteins in cluster 1 were characterized with the slowest turnover rates thus defined as extremely long-lived proteins (ELLPs). The median values are marked at the center. The boxes extend from the 25th to 75th percentiles. The upper or lower whiskers extend from the hinge to the largest or smallest value no further than 1.5 times the interquartile range (IQR).d Venn diagram and GO analysis of ELLPs in head and muscle. 149 ELLPs were found in both head and muscle, two post-mitotic tissues, and then subjected to functional analysis, with “nucleosome assembly” as the most significant hit (p = 5.2e-9, Fisher’s exact test). e H2A and H2B are ELLPs. H2A and H2B belonging to “nucleosome assembly” category were identified with a dramatic enrichment of 15N signals at day 60. The extracted ion chromatographs (XICs) of the paired 15N and 14N peaks from two representative peptides were comparedCC BY · PubMed Central
Fig. 2 Ubiquitylome analysis of the aging proteome in fly heads. a Proportions of 15N-PSMs in total PSMs. While 15N-labeled old forms accounted for 28% of the entire proteome at 60d, they represented 59% of the ubiquitylated proteome, suggesting increased ubiquitylation in older proteome. b Quantifications of 15N signals in total proteins and ubiquitylated proteins. A scatter plot of 15N ratio confirms a majority of the proteins have higher 15N proportion in ubiquitylome than that of the normal aging proteome at 60d of age (p = 2.2e-16, Mann–Whitney-Wilcoxon test). c, d Ubiquitylated histone proteins are featured by higher 15N ratios, including H2A (c) and H2B (d). The XICs of the paired 15N and 14N peaks were compared. e Quantification of 15N proportions and abundance of ubiquitylated sites. H2A has high-abundance in the level of ubiquitylation, as assessed by the PSM counts
Fig. 2 Ubiquitylome analysis of the aging proteome in fly heads. a Proportions of 15N-PSMs in total PSMs. While 15N-labeled old forms accounted for 28% of the entire proteome at 60d, they represented 59% of the ubiquitylated proteome, suggesting increased ubiquitylation in older proteome. b Quantifications of 15N signals in total proteins and ubiquitylated proteins. A scatter plot of 15N ratio confirms a majority of the proteins have higher 15N proportion in ubiquitylome than that of the normal aging proteome at 60d of age (p = 2.2e-16, Mann–Whitney-Wilcoxon test). c, d Ubiquitylated histone proteins are featured by higher 15N ratios, including H2A (c) and H2B (d). The XICs of the paired 15N and 14N peaks were compared. e Quantification of 15N proportions and abundance of ubiquitylated sites. H2A has high-abundance in the level of ubiquitylation, as assessed by the PSM countsCC BY · PubMed Central
Fig. 3 H2A mono-ubiquitylation increases with age in Drosophila, mouse, monkey, and human. a Alignment of amino acid sequence showing striking conservation of H2A in Drosophila, mouse, monkey, and human. b, d, f, h, j Western blotting (left) and quantification (right) show an evolutionarily conserved increase of ubH2A with age. Western blotting was from head tissues of 3d and 30d old male flies (n = 4 independent biological repeats) (b), brain and heart tissues of 5 months (n = 4) and 23 months (n = 4) old male mice (d, f), parietal lobes of young (n = 3) and old (n = 4) rhesus macaque (h), and prefrontal cortex of brain tissues of young (n = 7) and old (n = 7) male or female humans (j). The median values are marked at the center. The boxes extend from the 25th to 75th percentiles. The p-values are calculated by using the student t test. c, e, g, i MS quantifications confirm the increase of ubH2A with age in Drosophila (n = 3 independent biological repeats)(c), mouse brain (n = 4 for both young and old groups) (e), mouse heart (n = 4 for both young and old groups) (g), and monkey (n = 3 for young, n = 4 for old) (i). The ubH2A was measured by PRM-based targeted mass spectrometry method. Representative XICs of the y3 ion were shown. The quantification was done by using the summed intensities of y3, y4, y5, y6, and y7 ions. Data are shown as mean ± s.d. The p-values are calculated by using the student t test
Fig. 3 H2A mono-ubiquitylation increases with age in Drosophila, mouse, monkey, and human. a Alignment of amino acid sequence showing striking conservation of H2A in Drosophila, mouse, monkey, and human. b, d, f, h, j Western blotting (left) and quantification (right) show an evolutionarily conserved increase of ubH2A with age. Western blotting was from head tissues of 3d and 30d old male flies (n = 4 independent biological repeats) (b), brain and heart tissues of 5 months (n = 4) and 23 months (n = 4) old male mice (d, f), parietal lobes of young (n = 3) and old (n = 4) rhesus macaque (h), and prefrontal cortex of brain tissues of young (n = 7) and old (n = 7) male or female humans (j). The median values are marked at the center. The boxes extend from the 25th to 75th percentiles. The p-values are calculated by using the student t test. c, e, g, i MS quantifications confirm the increase of ubH2A with age in Drosophila (n = 3 independent biological repeats)(c), mouse brain (n = 4 for both young and old groups) (e), mouse heart (n = 4 for both young and old groups) (g), and monkey (n = 3 for young, n = 4 for old) (i). The ubH2A was measured by PRM-based targeted mass spectrometry method. Representative XICs of the y3 ion were shown. The quantification was done by using the summed intensities of y3, y4, y5, y6, and y7 ions. Data are shown as mean ± s.d. The p-values are calculated by using the student t testCC BY · PubMed Central
Fig. 4 Reducing ubH2A couples with extended adult lifespan in Drosophila. a Scec244/ + or Su(z)2c433/ + single mutants and Scec244/ + ; Su(z)2c433/ + double mutants have extended lifespan. All lifespan data of this study were acquired in at least two replicates. (For lifespan: 25 °C; n > 100 male flies per genotype for curve; log-rank test). Genotypes (fly total number (death / censored)): WT: 5905 (156 (154 / 2)). Scec244/ + (128 (113 / 15)). Su(z)2c433/ + (126 (111 / 15)). Scec244/ + ; Su(z)2c433/ + (144 (103 / 41)). b ubH2A is significantly decreased in Scec244/ + , Su(z)2c433/ + , and Scec244/ + ; Su(z)2c433/ + flies (n = 4 independent biological repeats for ubH2A quantification) (mean ± s.e.m.; student t test). Protein was from head tissues of 30d old male heads. c Volcano plot shows that genes are differentially expressed in Scec244/ + ;Su(z)2c433/ + double mutants compared to WT (left panel). Differential expression analysis was performed by DESeq2 from 3 biological replicates. 224 genes were found to be upregulated (Fold change > 1.5, p < 0.05). Ingenuity pathway analysis (right panel) shows that “glutathione-mediated detoxification” was significantly enriched for genes upregulated in the Scec244/ + ; Su(z)2c433/ + double mutant (p = 0.0026, Fisher’s exact test). RNA-seq was from heads of 30d old male flies. Genotypes: WT: 5905. Scec244/ + ; Su(z)2c433/ + . d qRT-PCR analysis shows that GSTO1 of the glutathione-mediated detoxification pathway becomes significantly increased in the Scec244/ + ; Su(z)2c433/ + double mutants (n = 3 independent biological repeats for qRT-PCR) (mean ± s.e.m.; student t test). qRT-RNA was from heads of 30d old male flies. Genotypes as in c. e While GSH and GSSG levels remain unchanged (left panel), GSH/(GSH + GSSG) ratio (right panel), indicator of the cellular redox level, is higher in Scec244/ + single mutants and Scec244/ + ; Su(z)2c433/ + double mutants than age-matched WT. Metabolic analysis was from heads of 30d old male flies. Genotypes: WT: 5905. Scec244/ + . Scec244/ + ; Su(z)2c433/ + (n = 3 independent biological repeats; student t test)
Fig. 4 Reducing ubH2A couples with extended adult lifespan in Drosophila. a Scec244/ + or Su(z)2c433/ + single mutants and Scec244/ + ; Su(z)2c433/ + double mutants have extended lifespan. All lifespan data of this study were acquired in at least two replicates. (For lifespan: 25 °C; n > 100 male flies per genotype for curve; log-rank test). Genotypes (fly total number (death / censored)): WT: 5905 (156 (154 / 2)). Scec244/ + (128 (113 / 15)). Su(z)2c433/ + (126 (111 / 15)). Scec244/ + ; Su(z)2c433/ + (144 (103 / 41)). b ubH2A is significantly decreased in Scec244/ + , Su(z)2c433/ + , and Scec244/ + ; Su(z)2c433/ + flies (n = 4 independent biological repeats for ubH2A quantification) (mean ± s.e.m.; student t test). Protein was from head tissues of 30d old male heads. c Volcano plot shows that genes are differentially expressed in Scec244/ + ;Su(z)2c433/ + double mutants compared to WT (left panel). Differential expression analysis was performed by DESeq2 from 3 biological replicates. 224 genes were found to be upregulated (Fold change > 1.5, p < 0.05). Ingenuity pathway analysis (right panel) shows that “glutathione-mediated detoxification” was significantly enriched for genes upregulated in the Scec244/ + ; Su(z)2c433/ + double mutant (p = 0.0026, Fisher’s exact test). RNA-seq was from heads of 30d old male flies. Genotypes: WT: 5905. Scec244/ + ; Su(z)2c433/ + . d qRT-PCR analysis shows that GSTO1 of the glutathione-mediated detoxification pathway becomes significantly increased in the Scec244/ + ; Su(z)2c433/ + double mutants (n = 3 independent biological repeats for qRT-PCR) (mean ± s.e.m.; student t test). qRT-RNA was from heads of 30d old male flies. Genotypes as in c. e While GSH and GSSG levels remain unchanged (left panel), GSH/(GSH + GSSG) ratio (right panel), indicator of the cellular redox level, is higher in Scec244/ + single mutants and Scec244/ + ; Su(z)2c433/ + double mutants than age-matched WT. Metabolic analysis was from heads of 30d old male flies. Genotypes: WT: 5905. Scec244/ + . Scec244/ + ; Su(z)2c433/ + (n = 3 independent biological repeats; student t test)CC BY · PubMed Central
Fig. 5 Reducing ubH2A couples with an effect to promote adult fitness. Analysis of adult phenotypes reveals that Scec244/ + single mutants and Scec244/ + ; Su(z)2c433/ + double mutants have better climbing (a) and enhanced resistance to oxidation (b) than age-matched WT. (for climbing assay: mean ± s.e.m. of 10 biological repeats with 10 male flies for each repeats; student t test; for oxidation tests: 25 °C, n > 100 male flies per genotype for curve, log-rank test). Genotypes (fly total number (death / censored)): WT: 5905 (196 (196 / 0)). Scec244/ + (245 (245 / 0)). Scec244/ + ; Su(z)2c433/ + (202 (201 / 1))
Fig. 5 Reducing ubH2A couples with an effect to promote adult fitness. Analysis of adult phenotypes reveals that Scec244/ + single mutants and Scec244/ + ; Su(z)2c433/ + double mutants have better climbing (a) and enhanced resistance to oxidation (b) than age-matched WT. (for climbing assay: mean ± s.e.m. of 10 biological repeats with 10 male flies for each repeats; student t test; for oxidation tests: 25 °C, n > 100 male flies per genotype for curve, log-rank test). Genotypes (fly total number (death / censored)): WT: 5905 (196 (196 / 0)). Scec244/ + (245 (245 / 0)). Scec244/ + ; Su(z)2c433/ + (202 (201 / 1))CC BY · PubMed Central

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Authors
Yang, L., Ma, Z., Wang, H., Niu, K., Cao, Y., Sun, L., Geng, Y., Yang, B., Gao, F., Chen, Z., Wu, Z., Li, Q., Shen, Y., Zhang, X., Jiang, H., Chen, Y., Liu, R., Liu, N., & Zhang, Y.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2019-05-21
Volume
10
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-019-10136-w
PMC
PMC6529468
Cited by
40
References
14
Language
en
Licence
Funders
National Natural Science Foundation of China (31671428, 31500665, 31530041)

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Yang, L., Ma, Z., Wang, H., Niu, K., Cao, Y., Sun, L., Geng, Y., Yang, B., Gao, F., Chen, Z., Wu, Z., Li, Q., Shen, Y., Zhang, X., Jiang, H., Chen, Y., Liu, R., Liu, N., & Zhang, Y. (2019). Ubiquitylome study identifies increased histone 2A ubiquitylation as an evolutionarily conserved aging biomarker. Nature Communications. https://doi.org/10.1038/s41467-019-10136-w