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Microarray Analysis of Early and Late Passage Chicken Embryo Fibroblast Cells1

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Microarray Analysis of Early and Late Passage Chicken Embryo Fibroblast Cells1 Microarray analysis of early and late passage chicken embryo fibroblast cells1 Byung-Whi Kong ,*2 Jeongyoon Lee ,* Walter G. Bottje ,* Kentu Lassiter ,* Jonghyuk Lee ,‡ Lauren E. Gentles ,† Yohanna G. Chandra ,* and Douglas N. Foster § * Department of Poultry Science, Center of Excellence for Poultry Science, and † Department of Biological Sciences, University of Arkansas, Fayetteville 72701; ‡ Department of Chemistry, Purdue University, West Lafayette, IN 47907; and § Department of Animal Science, University of Minnesota, St. Paul 55108 ABSTRACT Primary cultured cells derived from nor- functionally known genes and only 61 genes showed mal tissue have a limited lifespan due to replicative upregulation. Because senescent cells generally showed senescence and show distinct phenotypes such as ir- the deactivated states of most cellular mechanisms for reversible cell cycle arrest and enlarged morphology. proliferation and energy metabolism, intensified analy- Studying senescence-associated genetic alterations in sis on upregulated genes revealed that the molecular chicken cells will provide valuable knowledge of cellu- mechanisms in senescent CEF cells are characterized by lar growth characteristics, when compared with normal the suppression of cell cycle and proliferation, progres- and rapidly growing cell lines. Microarray analysis of sion of cell death including apoptosis, and increased early- and late-passage (passage 4 and 18, respectively) expression of various secreting factors. These regula- primary chicken embryo fibroblast (CEF) cells was per- tory pathways may be opposite to those found in the formed with a 4X44K chicken oligo microarray. A total immortal CEF cell line, such as the DF-1 immortal of 1,888 differentially expressed genes were identified line. Further comparison of differentially expressed with a 2-fold level cutoff that included 272 upregulated genes between senescent and immortal DF-1 CEF cells and 1,616 downregulated genes in late-passage senes- showed that 35 genes overlapped and were oppositely cent CEF cells. Bioinformatic analyses were performed regulated. The global gene expression profiles may pro- using Ingenuity Pathway Analysis (IPA, http://www. vide insight into the cellular mechanisms that regulate ingenuity.com). Of the 1,888 differentially expressed cellular senescence and immortalization of CEF cells. genes in senescent CEF cells, 458 were identified as Key words: senescence , chicken embryo fibroblast cell , microarray 2013 Poultry Science 92 :770–781 http://dx.doi.org/ 10.3382/ps.2012-02540 INTRODUCTION nescence, such as inactivation of p53, overexpression of p16INK4, and telomere regulatory functions, have Replicative senescence is known to be an intrinsic been well characterized in human and mouse fibroblast mechanism in determining the finite lifespan of normal cells (Sherr and DePinho, 2000). Most cells are unable cells cultured in vitro (Hayflick and Moorhead, 1961). to overcome senescence unless key tumor suppressor This process is recognized as an evolutionarily conserved pathways are first altered. Thus, cellular senescence has mechanism in eukaryotic cells. Senescent cells display been known to be a critical anticancer mechanism that distinct phenotypic characteristics, such as growth ar- suppresses cell growth at the risk for cellular transfor- rest, enlarged cell morphology, cell cycle arrest, and mation (Campisi, 2001). telomere shortening (reviewed in Rodier and Campisi, Traditionally, primary chicken embryo fibroblasts 2011). A variety of genetic and epigenetic changes that (CEF) have been used for vaccine production, al- include irreversible cell cycle arrest in replicative se- though primary CEF cells have the major disadvantage of inconsistent production of virus titer. Continuously © 2013 Poultry Science Association Inc. growing or immortal avian cell lines that are not the Received June 15, 2012. result of infection with oncogenic viruses or treatment Accepted October 26, 2012. 1 BWK designed the experiments, analyzed the data, and wrote the with carcinogenic chemicals but were established spon- manuscript; JYL performed the microarray experiments and analyzed taneously provide a stable supply of identical cells for data; WB and KL contributed to the bioinformatics analysis and man- vaccine production. Several spontaneously immortal- uscript editing; JL and LEG analyzed the qPCR assay; YGC analyzed ized CEF cell lines, such as the DF-1, SC-1, and SC-2 microarray data; and DNF prepared senescent cells and edited the manuscript. All authors read and approved the final manuscript. lines, have been established that may provide a consis- 2 Corresponding author: [email protected] tent cellular source of poultry infectious viruses (Himly 770 MICROARRAY ANALYSIS OF CHICKEN EMBRYO FIBROBLAST CELLS 771 et al., 1998; Christman et al., 2005, 2006). Interestingly, NC). Cultured cells were grown at 39°C in a 5% CO2 although most CEF cells entered a senescent state after incubator until cells reached confluence (2 to 4 d) and limited cell divisions, a small proportion of the cells primary CEF cells were passaged every 3 to 4 d for 2 regained their replication capacity and finally became mo until cells ceased growing. Cells collected at the immortalized. Theses observations suggest that the ac- fourth passage were designated as young CEF cells, cumulation of genetic alterations may allow a subpop- whereas those collected at the eighteenth passage were ulation of CEF cells to overcome cellular senescence designated as senescent CEF cells. All procedures for leading to immortalization. Although the alteration of handling chicken embryos, cell culture, and DNA/RNA p53, p16INK4, and telomere regulatory functions dur- isolation were approved by the Institutional Biosafety ing replicative senescence were demonstrated previous- Committee (IBC: protocol number: 10007) at the Uni- ly in primary CEF cells (Kim et al., 2002), the genome- versity of Arkansas. wide transcriptional alterations of senescent CEF cells have yet to be determined. Previously, we reported the global gene expression Total RNA Extraction profiles in spontaneously immortalized DF-1 CEF cells Total RNA was extracted from young (passage 4) showing enhanced proliferation rates, hypersensitiv- and senescence (passage 18) CEF cells using TRIzol ity to oxidative stress, and hyperactive mitochondrial reagent (Invitrogen Life Technologies, Carlsbad, CA) functions (Kim et al., 2001; You et al., 2004; Kong et following the manufacturer’s instructions. Total RNA al., 2011). The microarray data revealed that immor- was treated with DNase I (New England BioLabs Inc., tal DF-1 CEF cells were characterized by enhanced Ipswich, MA), and RNA was repurified by TRIzol re- molecular mechanisms for cell cycle progression and agent. proliferation, suppression of apoptosis, altered cellular morphogenesis, and accelerated capacity for molecule transport. The immortal DF-1 cell line was derived Probe Labeling and Microarray from CEF cells initially isolated from ev-0 (endogenous Hybridization virus free) embryos (Himly et al., 1998). Moreover, the DF-1 cell genome is currently being sequenced (person- The 4X44K Agilent chicken oligo microarray (array al communication, Jerry Dodgson, Michigan State Uni- ID: 015068) and a 2-color labeling microarray system versity, East Lansing). Therefore, the major objective kit (Agilent Technologies, Palo Alto, CA) was used to of the present study was to conduct defined epigenetic compare mRNA expression between young- and se- studies with primary nonsenescent (young), senescent, nescent CEF cells. Fluorescently labeled complemen- and DF-1 immortal CEF cells to specifically investi- tary RNA (cRNA) probes were generated following gate critical factors involved in modulation of cell pro- the manufacturer’s instructions. The RNA Spike-in liferation and lifespan. In this study, genome-wide dif- controls were used to adjust possible dye effects fol- ferential gene expression in senescent CEF cells was lowing the manufacturer’s instructions (Zahurak et al., determined using microarray analysis and was further 2007; Lee et al., 2010). Briefly, 2 µg of total RNA was compared (contrasted) with immortal DF-1 cells to in- converted to cDNA using reverse transcriptase and an vestigate potential genetic factors that could initiate oligo dT primer in which the T7 promoter sequence the immortal phenotype in chicken cells. was added. T7 RNA polymerase was used for the syn- thesis and labeling of cRNA with either Cy3 dye for the young CEF control or Cy5 dye for senescent CEF MATERIALS AND METHODS RNA samples. The concentration, fluorescent intensi- ties, and quality of labeled cRNA probes were deter- Cell Culture mined using a Nano-drop spectrophotometer (Thermo All materials and methods including cell culture, Scientific, Wilmington, DE). After hybridization, slides RNA isolation, microarray, reverse-transcription PCR, were scanned using a Genepix 4000B scanner (Molecu- and bioinformatics were followed as previously report- lar Devices Corporation, Sunnyvale, CA) with the tol- ed (Kong et al., 2011) with modifications. Briefly, cell erance of saturation setting of 0.005%. Four biological culture reagents were purchased from Invitrogen Life replicates were conducted. Technologies (Carlsbad, CA). Primary chicken CEF cells were isolated from 10-d-old specific-pathogen free Microarray Data Collection and Analysis (SPF) chicken embryos (Charles River Laboratories, North Franklin, CT). Single cell populations were ob- Background-corrected
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