Departments of 2 Cellular and Molecular Physiology, 1 Pediatrics, and 3 Anesthesia, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033
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ABSTRACT |
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Control of alveolar cell growth and differentiation after pneumonectomy likely involves changes in expression of regulatory genes, including those encoding zinc finger (ZF) proteins. To explore this premise, total RNA from the lungs of control and pneumonectomized rats was reverse transcribed; PCRs were performed with degenerate primers corresponding to amino acid sequences HTGEKP and CPECGK(N), which are evolutionarily conserved among ZF genes. Reaction products corresponding to three and four ZF units were isolated and cloned. Sixteen clones were sequenced and found to represent rat lung ZF genes: six clones were highly similar or identical to known ZF genes and ten clones showed lower homology to known ZF genes and thus appear to represent new members of the ZF family. Northern analysis demonstrated differential expression of some ZF genes after pneumonectomy. Thus a PCR-based strategy with primers derived from evolutionarily conserved ZF protein sequences efficiently identifies ZF genes expressed in lung, some of which may play a role in cellular growth and differentiation.
gene expression; lung growth; pneumonectomy; polymerase chain reaction; transcription factors
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INTRODUCTION |
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PRODUCTS OF MOST ZINC FINGER (ZF) genes act as negative
or positive transcriptional regulators of target gene expression (24, 33). The
C2-H2
family of ZF proteins share the consensus sequence Cys-Xaa2-4-Cys-Xaa3-Phe-Xaa5-Leu-Xaa2-His-Xaa3-5-His (5, 25). Pairs of cysteine (C) and histidine (H) residues coordinate
Zn2+ tetrahedrally, making a
structural unit for individual ZFs that consists of an -helix and an
antiparallel
-ribbon. ZF proteins bind DNA in a sequence-specific
fashion by insertion of the helix into the major groove of the DNA
molecule (26). The arrangement of individual ZFs is usually in a single
cluster with multiple repeats (11), although proteins containing
multiple-cluster ZFs (32), individual ZFs (1), or individual ZFs
dispersed throughout the protein (30) have been described.
More than 130 potential ZF loci have been identified in humans (2, 3, 23), where ZF genes may occupy >0.01% of the genome (2, 27). Mutation, disruption, and translocation of different ZF genes are associated with developmental disorders such as Greig cephalopolysyndactyly syndrome (37) and William's syndrome (36) as well as with malignancies including Wilm's tumor (15, 17), acute promyelocytic leukemia (7), and human lymphoma (20). These disorders involve abnormal regulation of cellular proliferation.
Cell proliferation and differentiation in the lung can be initiated by several forms of lung injury, leading to hyperplastic growth of cells in the alveolar region. On the basis of evidence derived from other tissues, changes such as these in response to injury are likely to involve altered expression of growth regulatory genes. Genes that encode ZF proteins are thus candidates for a role in the pathways of lung cell proliferation.
Based on the importance of ZF proteins in the regulation of gene expression and cellular growth, experiments were designed to identify and clone ZF genes expressed in rapidly growing lungs. A well-established model involving the induction of lung growth after pneumonectomy was selected for these studies. In a variety of species, rapid hyperplastic growth of lung tissue is initiated after resection of one or more lung lobes (see Ref. 16 for a review) In humans, this response appears to be present in infants and young children but absent in adults (6). In rats, removal of the left lung, which constitutes about one-third of total lung tissue (29), initiates compensatory growth rapid enough to restore normal total lung mass in as few as 4 days (14). Cellular and subcellular mechanisms that regulate lung growth after pneumonectomy are not well understood.
The long-term goal of the present research is to identify genes that are involved in regulation of lung cell proliferation during the early postpneumonectomy interval as well as to define the regulation and significance of their expression in normal lung. The immediate focus is to identify specific genes encoding proteins in the C2-H2 ZF family, a group of nucleic acid-binding proteins with regulatory properties. The present results demonstrate that application of novel PCR-based strategies with primers derived from evolutionarily conserved ZF protein sequences allows identification of new ZF genes that are differentially expressed in rat lungs after partial pneumonectomy.
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EXPERIMENTAL PROCEDURES |
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Surgical procedures and processing of tissue. Adult male Sprague-Dawley rats (200-250 g body weight; Charles River Laboratories) were subjected to left pneumonectomy under chloral hydrate anesthesia (7.2%, 300 mg/kg) as detailed elsewhere (29). One day after pneumonectomy, the remaining lung lobes were quickly removed, trimmed free of extraneous tissue, rinsed in ice-cold PBS, blotted on filter paper, and frozen in liquid nitrogen. Lungs from unoperated control animals were studied in parallel. Isolation of total RNA was performed according to the TriReagent (Molecular Research, Cincinnati, OH) protocol for subsequent use in PCR and/or Northern blot analysis of gene expression. For PCR experiments, DNA contamination was removed from total RNA with a Message Clean kit (GenHunter, Brookline, MA).
PCR amplification, cloning, and sequencing of ZF genes. RT was performed with 200 ng of total RNA as a template and (dT)16 oligonucleotide as a primer. RT reactions were carried out in the presence of 1.5 mM MgCl2, 1× PCR buffer (Perkin-Elmer, Foster City, CA), RNAsin (20 units; Perkin-Elmer), Moloney murine leukemia virus reverse transcriptase (200 units; Life Technologies, Gaithersburg, MD), and 10 mM deoxynucleoside triphosphate in a total volume of 20 µl according to the protocol of the manufacturer (Perkin-Elmer). After RT, 10 µl of the reaction mixture were used as a template for a subsequent PCR reaction with the addition of 9 µl of 10× PCR buffer (Perkin-Elmer), 9 µl of 2 mM deoxynucleoside triphosphate, and 100 pmol of each primer, ZF-1 and ZF-2 (below). Total MgCl2 concentration was 1.5 mM in the presence of 2.5 units of Taq polymerase (total reaction volume 100 µl). Primers for PCR were degenerate; both were derived from conserved amino acid sequences of ZF proteins: ZF-1 sense primer, 5'-TG(T,C)-CC(A,C,G,T)-GA(A,G)-TG(T,C)-GG(A,C,G,T)-AA-3' and ZF-2 antisense primer, 5'-GG(T,C)-TT(T,C)-TC(A,C,G,T)-CC(A,C,G,T)-GT(A,G)-TG-3'.
A series of preliminary experiments was performed to determine the optimal annealing temperatures for the PCR reactions. Based on the results of those experiments, the method of touchdown PCR was used to prevent mispriming of intended PCR products. This method, also known as "step-down" PCR, begins the PCR process at an annealing temperature 10°C higher than the targeted annealing temperature. The annealing temperature in each subsequent cycle is decreased by 1°C until the targeted annealing temperature is reached, which is the final annealing temperature in the remaining cycles. Touchdown PCR reactions were performed as follows: first cycle: melting, 99°C for 2 min; annealing, 58°C for 2 min; and extension, 72°C for 30 s. In subsequent cycles, the melting temperature was 94°C (30 s), and the annealing temperature, held for 2 min, was decreased by 1°C each cycle until it reached 48°C, which was the final annealing temperature for the remaining 29 cycles. The extension temperature was 72°C for 30 s. Thus the total number of cycles was 39. A final extension at 72°C for 5 min was performed after the last cycle.
PCR products were separated on 1.5% NuSieve agarose gel (FMC BioProducts, Rockland, ME); bands corresponding in size with three or four ZF units (~270 and 360 bp, respectively) were excised and recovered with GELase Gel-Digesting Preparation (Epicentre Technologies, Madison, WI). Recovered DNA was cloned into pCR-II cloning vector with the TA cloning protocol (Invitrogen, San Diego, CA).
All clones were sequenced two times from both directions with the Sequenase Version 2.0 DNA sequencing kit (United States Biochemical, Cleveland, OH) and the fmol DNA sequencing system (Promega). Sequence analysis was performed with the DNASTAR program on a Macintosh computer. Comparisons of the obtained sequences with those of known ZF proteins were accomplished with the GenBank and Swiss Protein databases. Sequence similarity searching was accomplished with the BLAST program.
Northern analysis. Total RNA samples
(20 µg) were denatured and size fractionated on 1.2% agarose gels
containing 0.4 M formaldehyde. Fractionated RNA was transferred to
nylon membranes (MSI, Westboro, MA) with downward capillary blotting,
and the blots were subsequently probed with radiolabeled riboprobes
corresponding to each rat lung ZF (RLZF) clone. Riboprobes were
synthesized by in vitro runoff transcription of linearized templates
with [-32P]UTP and
either T7 or Sp6 bacteriophage RNA polymerase according to the
MAXIscript protocol (Ambion, Austin, TX). The direction for antisense
RNA synthesis was determined by previous sequencing reactions. The
control probes used to normalize for differences in RNA included a
0.9-kb cDNA fragment of rat glyceraldehyde-3-phosphate dehydrogenase
and/or a 2-kb EcoR I
and/or Xho I cDNA fragment of
the rat homologue to prokaryotic elongation factor Tu (EFTu) (22).
Control probes were radiolabeled by random priming with [
-32P]dCTP
according to the DECAprime II protocol (Ambion).
Hybridization experiments were performed in a rolling incubator at
65°C overnight using prehybridization and hybridization sodium
phosphate-based solution. This solution consisted of 7% SDS, 0.5 M
Na2HPO4,
1% nonfat dry milk, and 1 mM EDTA. Washes were performed in 2×
saline-sodium phosphate-EDTA (0.3 M NaCl, 20 mM
NaH2PO4,
pH 7.4, and 20 mM EDTA, pH 7.4) containing 0.5% SDS at 65°C for 30 min. For autoradiography, the blots were exposed to Fuji RX film, with
intensifying screens, at 70°C. The Northern blots were
subsequently quantified with a Betascope 603 blot analyzer (Betagen,
Waltham, MA). Counts per minute associated with bands representing RLZF
products were compared with those of EFTu and/or glyceraldehyde-3-phosphate dehydrogenase to normalize for minor differences in the loading of RNA.
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RESULTS |
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Amplification of ZF sequences. A combination of biochemical and molecular approaches was applied to identify new ZF genes. The strategy took advantage of the existence of evolutionarily conserved sequences in known ZF proteins (Fig. 1). The first conserved sequence, the His-Cys link, separates tandem repeats of C2-H2 ZFs. The amino acid sequences HTGEKP, where H represents the second histidine of the C2-H2 repeat, and TGEKP, the His-Cys link, are conserved among the Krüppel subclass of ZF proteins. The second sequence, CPECGK(N), is also conserved among C2-H2 ZF proteins as part of a C2-H2 repeat.
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Annealing conditions were established by a series of preliminary PCR reactions at different annealing temperatures, namely, 42, 45, or 48°C for 2 min, each with radiolabeled primers. Products of these reactions were visualized on polyacrylamide gels (data not shown). PCR reactions performed with annealing temperatures of 42 or 45°C generated a wide spectrum of products evenly distributed across the gel. Reactions performed with an annealing temperature of 48°C also produced bands distributed throughout the gel. In the latter case, however, reaction products of ~90, 180, 270, and 360 bp, which represent multiples of ZF units, were predominant compared with other products of the reaction. On the basis of these observations, 48°C was selected as the ultimate annealing temperature, and the annealing reaction was continued for 2 min.
In conjunction, touchdown PCR (see EXPERIMENTAL PROCEDURES) was utilized to increase the specificity of the reaction and to prevent mispriming. The resulting PCR products were in the form of a ZF ladder (Fig. 2) where individual bands represent a different number of ZF units, each ~90 bp in length. PCR products corresponding in size to three and four ZF units were extracted and cloned. A total of 16 clones were sequenced: 8 from the lungs of unoperated control rats and 8 from the lungs of pneumonectomized rats.
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Analysis of PCR products. DNA sequences from the 14 unique clones are shown in Fig. 3. Partial sequences corresponding to the primers used in the PCR reaction are omitted. Corresponding theoretical amino acid sequences were derived for each clone using the conserved sequences CPECGK and HTGEKP for orientation of the reading frame (Fig. 4). The resulting amino acid sequences were analyzed by comparison to known ZF proteins and to each other.
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Analysis showed that all 16 clones are partial sequences of ZF coding genes with characteristic, evolutionarily conserved sequences. One clone (RLZF cl-15) had an amino acid sequence identical to that of the rat ZF protein ZF Kid-1 (38, 39). Two clones (RLZF cl-13 and RLZF cl-19) were identical to each other and displayed 96% homology with the mouse ZF protein ZFP-38 (9). Two more identical clones (RLZF cl-23 and RLZF cl-34) had 92% homology with the mouse protein ZFP-29 (10). An additional clone (RLZF cl-6) also showed 92% homology with ZFP-29, but its sequence was clearly different from both the DNA and amino acid sequences of clones RLZF cl-23 and RLZF cl-34 (Fig. 4). Ten clones (clones RLZF cl-7, RLZF cl-8, RLZF cl-9, RLZF cl-11, RLZF cl-27, RLZF cl-29, RLZF cl-31, RLZF cl-32, RLZF cl-33, and RLZF cl-35) exhibited 64-74% amino acid sequence homology to known ZF proteins, suggesting that they represent new ZF genes.
Further sequence analysis revealed that most RLZF clones have intact C2-H2 ZF structures, with well-preserved, evolutionarily conserved sequences HTGEKP and CPECGK(N) (Fig. 4). Sequences of several clones, however, exhibited variations on this pattern. For example, RLZF cl-9 exhibited a preserved C2-H2 structure until amino acid 49 (amino acid 52 of the consensus sequence in Fig. 4), followed by a spacer sequence unrelated to the sequences of the other clones, but then returned to the C2-H2 structure at position 84 (amino acid 90 of consensus sequence in Fig. 4). Similarly, RLZF cl-35 retained an intact C2-H2 structure until amino acid 49 (amino acid 52 of the consensus sequence in Fig. 4), followed by a spacer sequence poorly related to the sequences of the other RLZF clones. This sequence also returned to the C2-H2 structure at position 75 (amino acid 90 of the consensus sequence in Fig. 4). Spacer sequences such as these have been previously described (35); they may represent vestigial or inactivated ZFs (27). In contrast, the sequences of RLZF cl-8 and RLZF cl-13 have well-preserved C2-H2 sequences until amino acids 28 and 31, respectively. The remaining sequences of both clones correlate poorly with the sequences of other RLZF clones.
Effect of pneumonectomy on expression of ZF genes. On the basis of the potential role of ZF genes in the regulation of tissue growth, the right lungs of rats subjected to left pneumonectomy were screened for changes in expression of the RLZF clones. Left pneumonectomy increases the rate of right lung growth as much as eightfold compared with the lungs of control animals (29). Radiolabeled riboprobes synthesized from 14 unique RLZF clones were used to probe Northern blots prepared from the lungs of pneumonectomized animals 6 h and 1 and 3 days after surgery (Fig. 5). Control samples were derived from the lungs of contemporaneous sham-operated and from unoperated animals (Table 1).
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Hybridized mRNA transcripts ranged in size from ~2 to 4 kb. Expression of some RLZF clones was reduced after pneumonectomy, with the magnitude of change being dependent on the length of the postoperative interval. These reductions were sometimes associated with minor changes in sham-operated animals. Expression of several clones, however, revealed similar levels of reduction in expression after both pneumonectomy and a sham operation, suggesting that they are downregulated after surgery. None of the RLZF clones showed increased expression after either pneumonectomy or sham thoracotomy.
Tissue distribution of the RLZF clones. In addition to the lung, the rat heart, liver, kidney, and brain were screened for expression of the RLZF clones. Northern blot analysis demonstrated that all 14 unique clones are expressed in each of the 5 tissues. Relative levels of expression are more difficult to evaluate because expression of mRNAs specific to commonly employed control probes such as glyceraldehyde-3-phosphate dehydrogenase or EFTu differs greatly among these tissues. Alternatively, Northern blot data were normalized based on the staining of rRNA with ethidium bromide. This approach indicated that the clones are widely distributed across tissues of the rat, with levels of expression being comparable in the five tissues examined (data not shown).
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DISCUSSION |
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Identification of ZF genes. The results described in this study were obtained with a PCR-based cloning strategy designed to identify ZF genes expressed in the lung. In past studies, ZF genes have been identified both on the basis of their biological properties (34) and through targeted cloning strategies using cDNA libraries or genomic DNA (see Ref. 4 for a review; also Refs. 8, 21, 34). The efficiency of the latter approach is limited because it requires construction of either a cDNA or genomic DNA library and involves several cycles of screening to identify the products of interest. Due to these limitations, more efficient cloning strategies have recently been developed.
PCR amplification of ZF coding genes with primers derived from the evolutionarily conserved sequence HTGEKPXC (the "His-Cys link") has been reported. Pellegrino and Berg (27) applied this approach to human genomic DNA. Ten clones were sequenced, with each distinct clone representing a unique ZF coding gene. With the use of this type of strategy with genomic DNA as a template, it is not possible to determine whether the ZF sequences identified are expressed. In contrast, Furukawa et al. (13) used total RNA from growing erythropoietin-treated human K562 or MBO2 cells as a template in a PCR-based cloning strategy with evolutionarily conserved primers. Six of the twenty-one clones sequenced were ZF coding genes. Four clones were new ZF family members, and one was a known ZF gene; the remainder of the clones represented rRNA. Together these studies established the usefulness of PCR-based strategies for identification of novel genes encoding ZF proteins.
The aim of the present work was to isolate ZF encoding genes from rat lung tissue and to begin studies of their expression. The approach differed from those cited above (13, 27) in that it was designed to amplify only ZF genes that are expressed. In addition, specific modifications of the PCR strategy were made to allow the use of total RNA as template but to avoid amplification of rRNA. First, RT was performed with a (dT)16 primer rather than primers representing the conserved ZF sequences. This approach was used to avoid initial mispriming. Second, the "sense" primer was derived from the less conserved ZF sequence CPECGK(N) to ensure variability in products of the first PCR cycle.
The clones obtained exhibit characteristics common to other
C2-H2
ZF encoding genes, demonstrating high specificity of the PCR reactions
for ZF gene products. The fact that 14 of the 16 clones contained
unique sequences further suggests satisfactory variability among the
reaction products. Although it is not possible to argue definitively
against the possibility that minor differences between RLZF sequences
may be due to mutations during PCR or cloning, several aspects of the
results suggest specificity in the method. First, sequences of the
clones are short relative to the predicted frequency of polymerase
infidelity (2 × 104
nucleotides/cycle), reducing the probability of error in any given
clone. Second, the fact that some of the clones are either identical to
each other (RLZF cl-13 and RLZF cl-19; RLZF cl-23 and RLZF cl-34) or
highly homologous to the known ZF gene
Kid-1 (38) suggests reproducibility of
the data. In addition, the degree of variability in ZF coding sequences
among the RLZF clones is similar to that observed in ZF genes
previously reported (27).
The sequence results strongly suggest that at least 10 RLZF clones represent unique ZF genes. Although it is possible that some of the clones may represent different parts of the same gene, the functional significance of the variability in amino acid sequences cannot be resolved without cloning each gene in its entirety. In this context, the intent of the above analysis is to emphasize the utility of the approach and the variety of cloned genes.
Potential function of RLZF genes. All RLZF clones reported here contain an evolutionarily conserved sequence encoding a tandem array of C2-H2-rich finger domains (Fig. 4). This motif has been described in many previously isolated ZF genes including frog transcription factor IIIA (5, 25), Drosophila Krüppel gene (31), yeast ADR1 (18), and human Sp1 (19). Since the discovery of the first ZF protein, it has been suggested that the repeating C2-H2 unit might be common to many other proteins involved in the regulation of gene expression (25). Indeed, many of these proteins act as transcription regulatory factors. Most ZF proteins containing C2-H2-type ZFs have been shown in vitro to bind DNA and regulate transcription of target genes (12, 28). The presence of C2-H2 ZF coding domains in the RLZF clones strongly suggests that the corresponding proteins may act to bind DNA or RNA in a sequence-specific manner and regulate transcription.
Unilateral pneumonectomy initiates coordinated growth and division of a spectrum of cell types in the remaining lung, thus involving transcriptional regulation of a variety of gene products. The possibility that RLZF genes play a role in the compensatory growth response was addressed by analysis of their pattern of expression as a function of postoperative time. The majority of RLZF clones showed little or no change in expression after pneumonectomy. These results suggests that many of these RLZF genes could be important for transcriptional regulation of specific gene products involved in normal cell function. The fact that the RLZF clones were widely distributed across tissues of the rat supports this view.
In contrast, Northern analysis of four RLZF clones revealed downregulation after pneumonectomy (Table 1). ZF proteins can regulate transcription in either a positive or a negative fashion. Thus decreased expression of a transcriptional repressor would increase target gene expression and could contribute to compensatory lung growth. These preliminary results encourage further studies to define the role of altered RLZF gene expression in compensatory lung growth.
In conclusion, a selective, efficient method for isolation and identification of expressed ZF genes has been developed and applied to samples from rat lung tissue. The approach offers the advantages that it is rapid and straightforward, it does not amplify sequences of ribosomal origin, and it does not require differential hybridization or screening of a library. Furthermore, clones of interest, which may represent only a small portion of the entire gene product, can subsequently be used to generate probes to screen a cDNA library or to derive additional primers for use in PCR walking. The strategy was used to clone sequences that appear to represent 14 different ZF genes, 10 of which may be unique. These genes are expressed in the rat lung, heart, liver, kidney, and brain; several appear to be regulated differentially during the rapid phase of lung growth after pneumonectomy.
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ACKNOWLEDGEMENTS |
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We thank Suzanne P. Sass-Kuhn and Cara Martinez-Williams for excellent technical assistance.
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FOOTNOTES |
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This work was supported by National Heart, Lung, and Blood Institute Grants HL-20344 (to D. E. Rannels) and HL-08954 (to K. A. Gilbert).
Address for reprint requests: D. E. Rannels, Dept. of Cellular and Molecular Physiology, The Pennsylvania State Univ. College of Medicine C4723, 500 University Dr., Hershey, PA 17033.
Received 8 August 1997; accepted in final form 31 March 1998.
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