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3 Department of Nutrition and Health Sciences, University of Nebraska, Lincoln, NE 68583-0806; 4 Dipartimento delle Scienze Biologiche, Universitá di Napoli Federico II, Naples 80134, Italy; and 5 Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University Medical School, Saint Louis, MO 63101
* To whom correspondence should be addressed. E-mail: jzempleni2{at}unl.edu; eissenjc{at}slu.edu.
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ABSTRACT |
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Introduction |
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TOPABSTRACTIntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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, acetyl-CoA carboxylase ß, pyruvate carboxylase (PC)6, propionyl-CoA carboxylase (PCC), and 3-methylcrotonyl-CoA carboxylase. Carboxylases play essential roles in the metabolism of fatty acids, glucose, and some amino acids. The attachment of biotin to specific lysine (K) residues in carboxylases is catalyzed by holocarboxylase synthetase (HCS) in an ATP-dependent reaction (1). Recently, our view of potential biological functions of biotin has been expanded by the observation that histones contain covalently bound biotin (2,3). The following K residues in histones are targets for biotinylation: K9, K13, K125, K127, and K129 in histone H2A; K4, K9, and K18 in histone H3; and K8 and K12 in histone H4 (4–6). Evidence suggests that K8-biotinylated histone H4 and K12-biotinylated histone H4 are enriched in heterochromatin and participate in gene silencing (G. Camporeale, A. M. Oommen, J. B. Griffin, G. Sarath, and J. Zempleni, unpublished data). Moreover, the abundance of K8- and K12 biotinylated histone H4 is cell cycle dependent and reaches peak levels during mitotic chromatin condensation (7). Finally, K12-biotinylated histone H4 might participate in the cellular response to DNA double-strand breaks (8).
Histone biotinylation is mediated by HCS (9) and perhaps biotinidase (BTD) (3). Covalent modifications of histones are typically reversible (10); enzymes mediating debiotinylation of histones are largely unknown. Evidence suggests that BTD may mediate debiotinylation of histones (11) in addition to acting as a histone biotinyl transferase (3). It is uncertain how cells control these 2 opposing enzymatic activities of BTD. Variables such as the microenvironment in confined regions of chromatin, post-translational modifications of BTD, and alternate splicing of BTD might determine whether BTD acts as biotinyl histone transferase or histone debiotinylase (12). In addition, BTD-binding proteins might contribute to regulation.
The biotin protein ligases are evolutionarily conserved. A subset of these enzymes [exemplified by Escherichia coli biotin-protein ligase (BirA)] is known to function as transcriptional repressors (13,14). The effector of BirA transcriptional repression is biotinyl-5'-adenylate (bio-5'-AMP). The BirA-bio-5'-AMP complex is active in both enzymatic transfer of biotin and site-specific DNA binding. When biotin is abundant, BirA-bio-5'-AMP accumulates and binds to the operator sequence of the biotin biosynthesis operon to repress transcription. Thus, BirA couples the intracellular demand for and synthesis of biotin in E. coli. HCS is a structural and functional homolog of BirA (15,16).
Inborn mutations of human HCS and BTD decrease the histone biotinyl transferase activity of these enzymes (3,5,9). For example, biotinylation of histones is decreased in HCS-deficient human fibroblasts (5,9) and lymphoma (Jurkat) cells (G. Camporeale and J. Zempleni, unpublished data). Notwithstanding the potential importance of these observations, effects of hcs and btd gene mutations on chromatin structure and phenotypes are largely unknown.
The Drosophila melanogaster genome encodes orthologs of human HCS (GenBank accession no. AAF52022) and BTD (GenBank accession no. AAF46130). Consistent with this observation, all 5 major classes of histones are biotinylated in D. melanogaster (17). Biotin deficiency is associated with decreased lifespan and fertility in flies (17), but it remains uncertain whether this is caused by altered biotinylation of histones.
In this study, D. melanogaster was used as a model to investigate whether knockdown of HCS and BTD expression is associated with altered chromatin structure, as evidenced by decreased biotinylation of histone H3. Histone H3 was chosen as a model, because it is biotinylated more abundantly than other histones in flies (17). We used HCS- and BTD-deficient flies to investigate effects of altered histone biotinylation on phenotypes in flies. Here, we focused on lifespan and temperature tolerance as markers for phenotypic changes, given that previous studies linked biotin status to these variables (17). We identified genes whose expression is altered by loss of HCS expression.
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Materials and Methods |
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Generation of transgenic flies. HCS- and BTD-deficient flies were generated by using RNA interference (RNAi) by inserting gene-specific cassettes into the pUAST-sp plasmid (19). For generation of a vector targeting HCS, a 1.4-kb DNA fragment of the D. melanogaster CG14670 gene (coordinates 35696 to 37133, GenBank accession no. AE003602) was PCR amplified using the following PCR primers: EcoRI-5'-HCS (5'- ATATGAATTCGGAAGATTACGGTAAGCTAATTGC-3') and EcoRI-3'-HCS (5'-ATATGAATT CGCGACTTGGTGGACTCCTCGC-3') to generate the EcoRI-HCS-EcoRI cassette; and XbaI-5'-HCS (5'-CGCTCTAGATTACGGTAAGCTAATTGC-3') and Xho-3'-HCS (5'-CGCCTCGAGTGCGACTT GGTGGACTCC-3') to generate the XbaI-HCS-XhoI cassette. Both the EcoRI-HCS-EcoRI and the XbaI-HCS-XhoI cassettes were inserted as inverted repeats (IR) into the pUAST-sp vector to generate a plasmid denoted pUAST-IRsp-HCS; in the pUAST-IRsp-HCS plasmid the HCS cassettes are separated by a 200-bp spacer to enhance stability of the IR (19). For generation of a vector targeting BTD, a 1.5-kb DNA fragment of the D. melanogaster CG3599 gene (coordinates 300621 to 302187, GenBank accession no. AE003436) was PCR amplified using the following PCR primers: EcoRI-5'-BTD (5'-CGCGAATTCGCCGCCTCTGGTGATTCAATCC-3') and BglII-3'-BTD (5'-CGCAGATC TGTCAGTGCTCTTCAGCAGTTCG-3') to generate the EcoRI-BTD-BglII cassette; and XbaI-5'-BTD (5'-TTGTCTTGTCTAGATTATTCGCCGCC-3') and XhoI-3'-BTD (5'-CGCCTCGAGTGTCAGTG CTCTTCAGCAGTTCG-3') to generate the XbaI-BTD-XhoI cassette. Both the EcoRI-BTD-BglII and the XbaI-BTD-XhoI cassettes were inserted into the pUAST-sp vector as described above to generate a plasmid denoted pUAST-IRsp-BTD (19).
Germline transformations with pUAST-IRsp-HCS and pUAST-IRsp-BTD were conducted using P elements as described (20). In transformed flies, transcription of siRNA is driven by Gal4. Hence, the experiments described below were conducted by mating pUAST-IRsp-HCS and pUAST-IRsp-BTD transgenic virgin female flies to male Actin5C-Gal4 driver lines. Flies with straight wings produce siRNA and were selected for further experimentation. As a control, we used F1 crosses of wild-type (y w) virgin females with Actin5C-Gal4 male drivers (denoted as Actin5C-Gal4 control flies). The following additional controls were used in some experiments: Act5C-Gal4 driver flies; y w flies; and pUAST-IRsp-HCS and pUAST-IRsp-BTD flies that were not crossed with the Act5C-Gal4 driver.
D. melanogaster husbandry. Flies were housed at 25°C, fed cornmeal, and transferred to fresh tubes every 72 h unless noted otherwise. Flies were kept on a 12-h-light/-dark cycle.
Abundance of mRNA coding for HCS and BTD. Total RNA was isolated from 100 flies with TriZol reagent according to the manufacturer's instructions (Invitrogen). Genomic DNA was removed enzymatically using TURBO DNA-free (Ambion). Briefly, cDNA was synthesized using the ImProm-II reverse transcriptase system from Promega. Primers for HCS (forward primer = 5'-AGTATTGGAATTGGAGAATGC-3'; reverse primer = 5'-AACTTACATATTGATGGGAACC-3') and BTD (forward primer = 5'-CTACTACACCGATATACCCAGCAC-3'; reverse primer = 5'-CGCTGATGAAACAGTTGAGGAC-3') were designed using the Beacon designer 4.0 software (Premier Biosoft International). Real-time PCR was performed using the iCycler IQ multicolor real-time detection system (Bio-Rad). Histone H4 (GenBank accession no. NM_165383) was used as reference gene (forward primer = 5'-GTGCTGCGTGATAACATC-3'; reverse primer = 5'-TGGCTGTAACTGTCTTCC-3').
Biotinylated carboxylases.
The abundance of biotinylated carboxylases and the activity of PCC were quantified as markers for HCS deficiency in transgenic flies. Briefly, 50 flies were homogenized as described (17) and proteins (
100 µg) were resolved using 4–8% Tris-acetate gels (Invitrogen). Transblots were probed with streptavidin peroxidase (21). Band intensities were quantified by gel densitometry (22). Activity of PCC in fly homogenates was quantified as described (17).
BTD activity. Whole fly homogenates were prepared as described above; enzyme activity in homogenates was quantified by monitoring the BTD-mediated hydrolysis of biotinyl-p-aminobenzoic acid in a colorimetric assay (2).
HCS abundance. Abundance of HCS in whole fly homogenates was quantified by western-blot analysis using rabbit anti-human HCS (23); this antibody cross-reacts with HCS from D. melanogaster. Proteins were resolved using 4–8% Bis-Tris gels (Invitrogen) and transblots were probed with anti-HCS serum (20,000-fold dilution) and goat anti-rabbit IgG peroxidase conjugate (Sigma, 10 µg/L).
Biotinylated histones. We prepared histone extracts from whole fly homogenates as described (24), with minor modifications: 5 mol/L HCl was added to fly homogenates to produce a final concentration of 0.25 mol/L. Histones were extracted overnight (4°C); insoluble proteins were removed by centrifugation (10,000 x g; 10 min) and histones in the supernatant were precipitated with trichloroacetic acid (1.2 mol/L final concentration). Histones were washed with acetone and dissolved in 8 mol/L urea. Histones were resolved by gel electrophoresis (6) and probed using either streptavidin-peroxidase (2) or antisera (250-fold dilution) to K9-biotinylated histone H3 (K9BioH3) and K18-biotinylated histone H3 (K18BioH3) (5). Histone loading was equalized based on protein assays, densitometric quantitation of gels stained with Coomassie blue, and western-blot analysis using antibody to histone H3 C-terminal tail.
DNA microarray. RNA from 50 flies was extracted with 1 mL of TriZol reagent as described above. RNA was purified using the RNeasy mini kit (Qiagen) and hybridized to the D. melanogaster Genome 2.0 Array (Affymetrix) at the Genomics Core Research Facility, University of Nebraska-Lincoln (25). GeneChip operating software 1.4 (Affymetrix) was used for normalization and analysis of microarray data.
Lifespan. The lifespan of flies was determined as described previously, with minor modifications (17). Briefly, newly eclosed female and male flies were housed separately in groups of 20 flies per tube (n = 10 tubes per treatment group). Dead flies were counted and removed daily.
Temperature stress. Resistance of flies to cold and heat stress was determined as described previously, with minor modifications (17). In cold stress experiments, male and female flies were housed separately at 4°C for up to 16 h; at timed intervals, flies were transferred to room temperature and surviving flies were counted after 24 h. At each time point, 4 tubes (25 flies each) were collected (n = 4). For heat stress experiments, 4 tubes (25 flies each) were kept at 34°C for up to 9 h; dead flies were counted every 0.5 h.
Statistics. Homogeneity of variances among groups was tested using Bartlett's test (26). If variances were heterogeneous, data were log-transformed before further statistical analysis. Significance of differences among groups was tested by one-way ANOVA. Fisher's protected least significant difference procedure was used for post hoc testing (26). We analyzed effects of treatment over time (e.g. resistance to heat stress) by repeated measures of ANOVA. If effects of treatment over time were statistically significant, treatment effects at individual time points were assessed by one-way ANOVA and Fisher's protected least significant difference procedure for individual time points. We used StatView 5.0.1 (SAS Institute) to perform all calculations. Differences were considered significant if P < 0.05. Data are expressed as means ± SD.
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Results |
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TOPABSTRACTIntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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Biotinylation of histones. Previous studies provided evidence for gender specificity of histone biotinylation in flies (17). Hence, we investigated the effects of HCS and BTD knockdown on histone biotinylation separately for males and females. In males, both HCS and BTD deficiency caused a decrease in histone biotinylation. However, effects were more pronounced for HCS deficiency than for BTD deficiency. When biotinylated histones were probed with streptavidin-peroxidase as a general probe for biotin, the signal intensity was substantially decreased in HCS-RNAi flies and was moderately decreased in BTD-RNAi flies compared with Act5C-Gal4 controls (Fig. 4A). Biotinylated histone H4 was barely detectable in both transgenic flies and controls, consistent with previous studies in our laboratory (17). An unidentified biotinylated protein migrated between histones H1 and H3; this protein is denoted "unknown" in Figure 4A. Based on size and acid solubility of this protein, we speculate that this band corresponds to an unidentified species of biotinylated histone or histone variant. In contrast to males, HCS and BTD deficiency had only minor effects on biotinylation of histones in female flies (Fig. 4A).
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Theoretically, the small magnitude of effects of HCS and BTD deficiency in females compared with males could have been caused by inefficient knockdown of enzymes in females. We sought to exclude this possibility by quantifying the abundance of biotinylated carboxylases separately for males and females. The percent decrease of biotinylated carboxylases was similar in males and females. For example, the activity of biotinylated PC decreased by 90% in male and female HCS-deficient flies compared with Act5C-Gal4 controls. Likewise, the abundance of biotinylated PC decreased by about 50% in male and female BTD-deficient flies compared with controls (data not shown). These data suggest that the quantitatively minor decrease of biotinylated histones in female HCS-RNAi and BTD-RNAi flies compared with males was not caused by insufficient knockdown of HCS and BTD.
Gene expression is affected by HCS deficiency. We used expression profiling of knockdown flies to look for evidence that patterns of gene expression were altered in response to changes in chromatin modification. As a model, we selected the treatment group that exhibits the greatest alteration of histone biotinylation in the above experiments: HCS-deficient male flies. Gene expression profiles in these flies and Act5C-Gal4 controls were obtained by using DNA microarrays. The expression of 77 genes decreased by at least 50% in HCS-RNAi flies compared with Act5C-Gal4 controls, whereas the expression of 124 genes increased by at least 100% compared to controls (supplemental Table 1). We observed some clusters of HCS-dependent genes, based on biological process and molecular function. For example, HCS deficiency was associated with substantially increased expression of genes that play roles in signal transduction, transport, and cell death, and was associated with substantially decreased expression of genes that play roles in defense response (Table 1).
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Discussion |
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TOPABSTRACTIntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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Expression of HCS and BTD was dramatically knocked down by RNAi, as judged by the abundance of mRNA coding for HCS and BTD, levels of HCS protein and biotinylated carboxylases, and activity of BTD. HCS deficiency was associated with a global decrease in histone biotinylation and also with a decrease of specific biotinylation sites in histone H3. The reduction in histone biotinylation seen in HCS knockdown flies is consistent with our finding that HCS is a chromosomal protein and suggests that the effect is direct. Effects of HCS deficiency on histone biotinylation were more modest in females than in males. Generally, effects of BTD deficiency on histone biotinylation are smaller than the effects observed for HCS deficiency. However, the fact that both knockdowns have pronounced effects demonstrates that these proteins have at least some nonredundant activity in vivo.
Both HCS and BTD deficiency decrease histone biotinylation to a greater extent in males than in females. The reason for this gender specificity is unknown. We excluded the possibility of insufficient knockdown of HCS and BTD in females by demonstrating that biotinylated carboxylases were decreased to a similar level in transgenic flies of both genders. Why, then, is histone biotinylation decreased to a greater extent in males than in females? One possibility is that the nuclear translocation of biotin might be more efficient in females than in males or that the turnover of biotinylated histones might be greater in males than in females. Another possibility is that the Y chromosome, which is male-specific and is entirely heterochromatic in somatic tissue, represents a major target for histone biotinylation in D. melanogaster; reduction of either HCS or BTD would thus be expected to have a disproportionate effect in males. Finally, we cannot exclude the possibility that a deficiency of either of the 2 histone biotinyl transferases was compensated for by the other biotinyl transferase in females. We sought to investigate this possibility by creating HCS and BTD double knockdowns. However, these flies were nonviable.
Previous studies provided evidence for roles of histone biotinylation in cell proliferation (2,7), DNA repair (8,30), and gene silencing (G. Camporeale, A. M. Oommen, J. B. Griffin, G. Sarath, and J. Zempleni, unpublished data). Consistent with the biological significance of these processes, a previous study suggested that biotin deficiency decreases lifespan and fertility in flies (17). However, in this previous study, a clear link of biotin deficiency and lifespan to histone biotinylation was not evident. To our knowledge, we provide here for the first time evidence that reduced biotinylation of histones in HCS-deficient flies is linked to phenotypes such as decreased lifespan and heat tolerance. Also, we provide evidence that alterations of chromatin structure by decreased biotinylation of histones is associated with unique patterns of gene expression. Gene expression analysis indicates that HCS deficiency alters the expression of 201 genes. We also identified 285 heat-responsive genes that depend on HCS for normal expression. Currently, it is unknown which of these genes mediate the increased heat susceptibility in HCS-deficient flies.
A caveat to these findings is that HCS and BTD deficiency decreases biotinylation of both histones and carboxylases. Theoretically, some of the effects described here might be due to decreased biotinylation of carboxylases rather than histones. To address this uncertainty, we are currently investigating genotypes and phenotypes of flies in which individual carboxylases were knocked down. These ongoing studies provided evidence that knockdown of PC and 3-methylcrotonyl-CoA carboxylase is not associated with increased susceptibility to heat stress (G. Camporeale, J. C. Eissenberg, and J. Zempleni, unpublished data). Based on these ongoing studies, we hypothesize that the increased heat susceptibility observed in HCS-deficient flies is a direct result of changes in histone biotinylation and chromatin structure rather than being a result of secondary changes due to reduced activities of biotin-dependent enzymes.
The hypothesis that many of the effects of HCS and BTD deficiency act at the level of chromatin modification offers a novel explanation for the diverse and apparently unrelated deficits seen in HCS and BTD deficiency in patients. Rather than being connected through metabolic pathways, as in classical vitamin deficiencies, the symptoms of HCS and BTD deficiency may reflect, to a significant degree, the misregulation of genes connected by their use of histone biotinylation as a regulatory mechanism. The development of D. melanogaster models for HCS and BTD deficiency, combined with the favorable cytology and genetics of D. melanogaster, will help define the role of histone biotinylation in gene regulation and disease.
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FOOTNOTES |
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2 Supplemental Tables 1 and 2 are available with the online posting of this paper at jn.nutrition.org.
6 Abbreviations used: BirA, biotin-protein ligase; BTD, biotinidase; FITC, fluorescein isothiocyanate; HCS, holocarboxylase synthetase; K9BioH3, lysine-9 biotinylated histone H3; K18BioH3, lysine-18 biotinylated histone H3; IR, inverted repeat; K, lysine; PC, pyruvate carboxylase; PCC, propionyl-CoA carboxylase; RNAi, RNA interference; y w, wild type.
Manuscript received 26 June 2006. Initial review completed 2 August 2006. Revision accepted 17 August 2006.
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LITERATURE CITED |
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1. Camporeale G, Zempleni J. Biotin. In: Bowman BA, Russell RM, editors. Present knowledge in nutrition. 9th ed. Washington: International Life Sciences Institute; 2006 (in press).
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5. Kobza K, Camporeale G, Rueckert B, Kueh A, Griffin JB, Sarath G, Zempleni J. K4, K9, and K18 in human histone H3 are targets for biotinylation by biotinidase. FEBS J. 2005;272:4249–59.[Medline]
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20. Spradling AC. P element-mediated transformation. In: Roberts DB, editor. Drosophila, a practical approach. Oxford: IRL Press; 1986. p. 175–97.
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