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© 2007 American Society for Nutrition J. Nutr. 137:885-889, April 2007

Biochemical, Molecular, and Genetic Mechanisms

Susceptibility to Heat Stress and Aberrant Gene Expression Patterns in Holocarboxylase Synthetase-Deficient Drosophila melanogaster Are Caused by Decreased Biotinylation of Histones, Not of Carboxylases1,2

Gabriela Camporeale3, Janos Zempleni3,* and Joel C. Eissenberg4,*

3 Department of Nutrition and Health Sciences, University of Nebraska, Lincoln, NE 68583-0806 and 4 Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University Medical School, St. Louis, MO 63101

* To whom correspondence should be addressed. E-mail: jzempleni2{at}unl.edu or eissenjc{at}slu.edu.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Previously, we discovered that holocarboxylase synthetase (HCS) is a chromatin-associated protein in Drosophila melanogaster and that HCS deficiency alters chromatin structure and gene expression patterns, leading to decreased heat tolerance. The effects of HCS deficiency were attributed to decreased biotinylation of histones. However, HCS is known to mediate biotinylation of carboxylases in cytoplasm and mitochondria in addition to mediating biotinylation of histones. A challenge posed by the genetic analysis of HCS is to distinguish between the effects of decreased biotinylation of carboxylases from the effects of decreased histone biotinylation in the gene expression patterns and phenotypes observed in HCS-deficient flies. Here, we tested whether 3-methylcrotonyl-CoA carboxylase (MCC) mutant flies exhibit gene expression patterns and heat susceptibility similar to that in HCS-deficient Drosophila. Biotin transporter [sodium-dependent multivitamin transporter (SMVT)] mutants were used to investigate effects of cellular biotin depletion on gene expression and heat susceptibility. Deficiencies of MCC and SMVT in mutant flies were confirmed by real-time PCR, streptavidin blotting of holocarboxylases, and analysis of MCC activities; expression of HCS and biotinylation of histones were not altered in MCC and SMVT mutants. Gene expression patterns in MCC and SMVT mutants were different from that seen with HCS-deficient flies, as judged by the abundance of mRNA coding for defective chorion 1, chitin-binding peritrophin-A, dopamine receptor 2, and yolk protein 2. MCC mutants exhibited increased resistance to heat stress compared with wild-type flies. We conclude that gene expression patterns and phenotypes in HCS-deficient flies in previous studies are caused by decreased biotinylation of histones rather than MCC.


   Introduction
TOP
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Biotin uptake into eukaryotic cells is mediated by the sodium-dependent multivitamin transporter (SMVT)5 (1). Intracellular biotin is then conjugated to carboxylases and histones by holocarboxylase synthetase (HCS) in an ATP-requiring reaction (2,3). Five biotin-dependent carboxylases have been identified: acetyl-CoA carboxylase {alpha}, acetyl-CoA carboxylase ß, pyruvate carboxylase (PC), propionyl-CoA carboxylase, and 3-methylcrotonyl-CoA carboxylase (MCC). These carboxylases play essential roles in intermediary metabolism. For example, PC and MCC catalyze steps in gluconeogenesis and leucine metabolism, respectively (2). The biological functions of carboxylases are distinct from the second family of biotinylated proteins, histones. Histones comprise 5 major classes (H1, H2A, H2B, H3, and H4) of DNA-binding proteins that play essential roles in chromatin structure, DNA repair, and gene regulation (4). Ten distinct lysine residues in histones H2A, H3, and H4 (5–7) are known to be targets for biotinylation in both humans and Drosophila melanogaster (8,9). Biotinylation of histones has been implicated in the cellular response to DNA double-strand breaks (10), cell proliferation and mitotic chromatin condensation (8,11), and heterochromatin structures and gene silencing in humans (12).

As of today, no HCS null individuals have been identified in the general population, consistent with essentiality of HCS-dependent biotinylation reactions and fetal lethality of the HCS null genotype. The prevalence of hcs gene mutations that cause decreased (as opposed to a lack of) HCS activity is also low in the general population, e.g. <1 in 100,000 live births in Japan (13). Symptoms of HCS deficiency include excretion of abnormal organic acids in the urine, skin rashes, and developmental delays (13,14). Afflicted individuals typically respond well to administration of pharmacological doses of biotin, in particular if the mutation of the gene resides in the sequences encoding biotin-binding region of the protein (13).

Recently, we showed that HCS is a chromatin-associated protein in Drosophila. We used RNAi to generate HCS-deficient Drosophila for the investigation of biological functions of HCS and biotinylated histones (15). We showed that HCS deficiency affects the extent of histone biotinylation and gene expression patterns and results in flies that have decreased heat tolerance. Notwithstanding the importance of these previous studies, the possibility was not formally excluded that decreased biotinylation of carboxylases, rather than decreased histone biotinylation, caused the gene expression and phenotypic changes observed in HCS-deficient flies. This uncertainty was addressed in our study. Specifically, we tested whether mutations in the gene coding for MCC caused gene expression patterns and heat susceptibility similar to those observed in HCS-deficient Drosophila; in addition, we used SMVT mutants to investigate effects of cellular biotin depletion on gene expression and heat susceptibility.

The selection of mutants was based on the following lines of reasoning. First, MCC mutants were selected because only a very small number of human cases of deficiency have ever been reported for this carboxylase (16–19). This observation suggests that null mutations of MCC are lethal and, thus, that MCC activity is essential for normal biotin metabolism. Second, an SMVT mutant was selected because deficiency of this transporter decreases uptake of biotin into eukaryotic cells, leading to moderate biotin depletion (20). Previous studies in our laboratory showed that moderate biotin deficiency is associated with selective depletion of biotinylated carboxylases, whereas biotinylation of histones is maintained at normal levels in human cells and Drosophila (9,21–23) under such conditions. Hence, SMVT deficiency is a model for moderate biotin deficiency that does not detectably impair chromatin structure.


   Materials and Methods
TOP
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 LITERATURE CITED
 
    Drosophila stocks. MCC (PBac{GAL4D,EYFP}CG2118PL00054) and SMVT (PBac{RB}CG2191e01332) mutant Drosophila melanogaster were obtained from the Bloomington Stock Center. In addition, a PC (P{w[+mGT] = GT1}CG1516BG01252) mutant stock was tested, but the decrease of PC expression in these flies was insufficient to permit meaningful analysis (see below). A laboratory strain of wild-type flies was used as control; in addition, HCS-deficient flies (denoted "HCS-RNAi") were generated by RNA interference (15) and were used as controls in some experiments.

    Drosophila husbandry. Flies were housed at 25°C on a standard cornmeal diet (9,24) and were transferred to fresh tubes every 72 h. The diet contained ~60 pmol biotin/g (9). Flies were kept on a 12-h-light/-dark cycle.

    Expression of HCS, MCC, PC, and SMVT. 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. PCR primers for HCS, MCC, PC, and SMVT (Supplemental Table 1) 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) using histone H4 as reference gene.

    Biotinylated carboxylases. The abundance of holocarboxylases and the activities of PC and MCC were quantified to estimate levels of gene knockdown in mutant flies. Briefly, 50 flies were homogenized as described (9) 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 (25). Note that MCC and propionyl-CoA carboxylase contain biotinylated and nonbiotinylated subunits and that only the biotin-containing {alpha} subunits are detectable in streptavidin blots. {alpha}-Subunits of MCC and propionyl-CoA carboxylase comigrated under the conditions used here. Activities of PC and MCC in fly homogenates were quantified, as described (26), with minor modifications (9).

    HCS abundance. Abundance of HCS in whole fly homogenates was quantified by Western-blot analysis using rabbit anti-human HCS (5); this antibody cross-reacts with HCS from Drosophila. 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 immunoglobulin G peroxidase conjugate (Sigma; 10 µg/L). Histone H3 was used as loading control, as described (15).

    Biotinylated histones. Drosophila histones were extracted as described (15). Histones were resolved by gel electrophoresis and probed using either streptavidin-peroxidase or antiserum to K18-biotinylated histone H3 (15). Equal loading of lanes was confirmed by using bicinchoninic assay (Pierce), densitometric quantitation of gels stained with Coomassie Blue, and Western-blot analysis using an antibody to the C terminus in histone H3.

    Gene expression patterns. HCS deficiency in flies is associated with altered expression of ~200 genes (15); here, we selected the following HCS-dependent genes for comparing gene expression patterns of carboxylase mutants and SMVT mutants to that of HCS-deficient flies: 1) defective chorion 1 (GenBank NP_511072) and chitin-binding peritrophin-A (CG9307), the expression of which is known to increase by 100–200% in HCS-deficient flies compared with wild-type controls (15); and 2) yolk protein 2 (CG2979) and dopamine receptor 2 (CG18741), the expression of which is known to decrease by 50–75% in HCS-deficient flies compared with wild-type controls (15). Here, we quantified the relative abundance of these HCS-dependent genes in MCC and SMVT mutants, HCS-RNAi transgenic flies (15), and wild-type controls. The goal was to determine whether gene expression patterns were similar in MCC and SMVT mutants compared with HCS-deficient flies. mRNA was quantified by real-time PCR as described above by using gene-specific primers (online Supplemental Table 1).

    Heat tolerance. Previous studies suggested that HCS-deficient flies have an increased susceptibility to heat stress (15). Here, we determined whether carboxylase and SMVT mutants have a phenotype similar to HCS-deficient flies. In heat stress experiments, 4 tubes (25 flies each) were kept at 34°C up to 9 h; dead flies were counted every 0.5 h. Data are presented in units of "% survival time." For example, the 75% survival time indicates the time of heat exposure that was survived by 75% of flies.

    Statistics. Homogeneity of variances among groups was tested using Bartlett's test (27). Significance of differences among groups was tested by 1-way ANOVA. Fisher's protected least significant difference procedure was used for post hoc testing (27). Effects of treatment over time (e.g. resistance to heat stress) were analyzed by repeated measures ANOVA. If effects of treatment over time were significant, treatment effects at individual time points were assessed by 1-way ANOVA and Fisher's protected least significant difference procedure for individual time points. StatView 5.0.1 (SAS Institute) was used to perform all calculations. Differences were considered significant if P < 0.05. Data are expressed as means ± SD.


   Results
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 LITERATURE CITED
 
    Expression and activities of carboxylases in MCC, and SMVT mutant flies. Expression of MCC and SMVT was substantially decreased in mutant flies compared with wild-type controls. This conclusion was based on the following observations. First, the abundance of MCC mRNA was decreased by 67 ± 0.8% in MCC mutants compared with wild-type flies (P < 0.02; n = 3). Likewise, the abundance of SMVT mRNA was decreased by 68 ± 6.0% in SMVT mutants compared with wild-type flies (P < 0.05; n = 3). In contrast, the abundance of PC mRNA was decreased by only 28 ± 2.1% in PC mutants compared with wild-type flies (P < 0.05; n = 3). This relatively moderate decrease of PC expression was further confirmed by analysis of PC activity (see below) and was the reason for excluding PC mutant flies from the majority of further analyses.

Second, the abundance of holocarboxylases was reduced in mutant flies compared with wild-type controls. Specifically, holo-MCC was barely detectable in MCC mutants compared with wild-type flies; for unknown reasons, the abundance of holo-acetyl-CoA carboxylase was moderately decreased in MCC mutants, whereas the abundance of holo-PC was not affected (Fig. 1; Table 1). Mutation of the smvt gene caused decreased abundance of holo-acetyl-CoA carboxylase, holo-MCC, and holo-PC. This observation is consistent with cellular biotin depletion by transporter deficiency.


Figure 1
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  		Figure 1  Mutations of mcc and smvt genes decreased the abundance of holocarboxylases in Drosophila melanogaster. Holocarboxylases in fly extracts were probed by using streptavidin peroxidase. PCC = Propionyl-CoA carboxylase.

 

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  		TABLE 1 Mutations of mcc, pc, and smvt genes decreased the abundance of holocarboxylases in Drosophila melanogaster1

 
Third, the activity of MCC was significantly lower in both MCC and SMVT mutants compared with wild-type controls (Fig. 2). These findings suggest that this mutant allele of mcc decreases the expression of MCC protein and that the mutant allele of smvt impairs cellular biotin uptake, leading to decreased carboxylase activities. In contrast, PC activity in PC mutants was decreased only moderately, by 30 ± 1.2% compared with wild-type flies (P < 0.05; n = 3). Note that all 3 of these mutant lines were identified based on P-element transposon insertions at the respective loci. To our knowledge, these are the first functional assays for each of these mutant alleles.


Figure 2
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  		Figure 2  Mutations in mcc and smvt genes decreased activities of MCC in Drosophila melanogaster. Values are means ± SD, n = 3. Means without a common letter differ, P < 0.05.

 
    Expression of HCS and biotinylation of histones. MCC and SMVT mutants expressed normal levels of HCS and exhibited a normal abundance of biotinylated histones. This conclusion is based on the following observations. First, the abundance of HCS mRNA in MCC and SMVT mutants was within 93–104% of the abundance in wild-type flies. Second, the abundance of HCS protein and histone H3 (control) was similar in mutants and wild-type flies (Fig. 3A). Third, the abundance of biotinylated histones was similar in carboxylase and SMVT mutant males and females compared with wild-type controls (Fig. 3B). Our observation that histone biotinylation remains unaltered despite SMVT deficiency is consistent with previous studies (9,21–23) showing that moderately biotin-deficient mammalian cultured cells maintain normal histone biotinylation (see Discussion).


Figure 3
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  		Figure 3  Mutations in mcc and smvt genes did not affect the abundance of HCS (panel A) and biotinylated histones (panel B) in Drosophila melanogaster. Histone H3 was used as a loading control.

 
    Gene expression patterns. MCC and SMVT mutants exhibited gene expression patterns that were different from the patterns known from HCS-deficient flies in previous studies (15). The expression of HCS-dependent genes (see Materials and Methods) was not affected by deficiencies of MCC or SMVT. For example, the abundance of mRNA coding for defective chorion 1 and chitin-binding peritrophin-A increased significantly in HCS-deficient flies compared with wild-type controls but was not altered in MCC and SMVT mutants (Fig. 4A). Likewise, the abundance of mRNA coding for yolk protein 2 and dopamine receptor 2 decreased significantly in HCS-deficient flies compared with wild-type controls but was not altered in MCC and SMVT mutants (Fig. 4B).


Figure 4
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  		Figure 4  Mutations in mcc and smvt genes did not affect the relative abundance of mRNA coding for defective chorion 1 and chitin-binding peritrophin 1 (panel A) and Yolk protein 2 and dopamine receptor 2 (panel B) in Drosophila melanogaster. Wild-type flies and HCS-deficient flies (HCS-RNAi) were used as controls. mRNA abundance in wild-type flies was set at 1. Values are means ± SD, n = 3. Means without a common letter differ, P < 0.05.

 
    Heat tolerance. Mutation of mcc was associated with increased tolerance to heat stress in both male and female flies compared with wild-type controls (Table 2). Mutations of the smvt gene did not affect heat tolerance. These phenotypes contrast with the decreased thermotolerance observed for HCS-deficient flies in previous studies (see Discussion).


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  		TABLE 2 Mutation of mcc gene but not the smvt gene increased heat tolerance in Drosophila melanogaster1

 

   Discussion
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
LITERATURE CITED
 
Here, we demonstrate that gene expression patterns and phenotypes of MCC-deficient and SMVT-deficient Drosophila are distinct from those observed with HCS-deficient flies. This is a critical observation in the context of our previous work, in which we characterized patterns of gene expression and heat susceptibility in HCS-deficient flies (15). In these previous studies, we proposed that gene expression patterns and phenotypes of HCS deficiency were caused by altered histone biotinylation and chromatin structure. Note that HCS deficiency decreases the abundance both of biotinylated histones and of biotinylated carboxylases. In this study, we formally excluded the possibility that decreased biotinylation of MCC explains gene expression patterns and phenotypes observed in HCS-deficient flies. This conclusion is based on the following observations: 1) patterns of gene expression are different in MCC mutants compared with HCS-deficient flies; and 2) heat tolerance increased in MCC mutants but decreased in HCS-deficient flies. Taken together, these findings support recent proposals that a major function of HCS is to mediate chromatin remodeling events.

Theoretically, both SMVT mutants and HCS-deficient flies could have an impaired ability to biotinylate carboxylases and histones. In SMVT mutants, impaired biotinylation of proteins is due to low cellular levels of biotin, as previously described for humans (28); in HCS-deficient flies, impaired biotinylation of proteins is due to low biotinyl protein ligase activity. One might speculate that SMVT mutants and HCS-deficient flies would exhibit similar gene expression patterns and phenotypes, if these variables were regulated by protein biotinylation. However, this study provides evidence that gene expression and phenotypes are different in SMVT mutants and HCS knockdowns. We offer the following explanation for this observation. SMVT deficiency is associated with impaired cellular uptake of biotin (20), causing moderate rather than severe biotin depletion in SMVT mutant flies. For example, abundance and activities of holo-carboxylases decreased by only 20–30% in SMVT mutants compared with controls. Previous studies suggested that moderate biotin deficiency was associated with depletion of holo-carboxylases whereas biotinylation of histones is maintained at normal levels in human cells and flies (9,21–23). This selective preservation of histone biotinylation over carboxylase biotinylation was confirmed in this study, where histone biotinylation was not altered in SMVT mutants. Collectively, the protein biotinylation patterns in SMVT mutants are similar to carboxylase mutants but distinct from HCS-deficient flies. Based on these patterns, it is not surprising that gene expression patterns and phenotypes in SMVT mutants resemble those in carboxylase mutants but are distinct from those in HCS-deficient flies.

Drosophila melanogaster has proven a useful model to study biological functions of HCS in chromatin remodeling, mediated by biotinylation of histones. We have generated novel tools for the investigation of biotin-dependent chromatin remodeling, including transgenic flies, human cells, and histone biotinylation site-specific antibodies. Now that these tools are in hand and gene expression patterns and phenotypes of HCS deficiency have been characterized, an important next step is to identify the mechanisms involved in chromatin remodeling by biotin. Currently, we are pursuing this goal by employing a variety of techniques, including studies of protein-protein interactions, chromatin immunoprecipitation assays, Drosophila genetics, and biotin feeding studies.


   FOOTNOTES
 
1 Supported by the University of Nebraska Agricultural Research Division, in part by funds provided through the Hatch Act. Additional support was provided by NIH grants DK 063945 and ES 015206-01, USDA grant 2006-35200-01540, and by NSF grants EPSCoR EPS-0346476, MCB 0131414, and MCB 6552870. Back

2 Supplemental Table 1 is available with the online posting of this paper at jn.nutrition.org. Back

5 Abbreviations used: HCS, holocarboxylase synthetase; MCC, 3-methylcrotonyl-CoA carboxylase; PC, pyruvate carboxylase; SMVT, sodium-dependent multivitamin transporter. Back

Manuscript received 20 November 2006. Initial review completed 29 December 2006. Revision accepted 3 January 2007.


   LITERATURE CITED
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
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