A gene expression signature shared by human mature oocytes and embryonic stem cells
© Assou et al; licensee BioMed Central Ltd. 2009
Received: 03 June 2008
Accepted: 08 January 2009
Published: 08 January 2009
The first week of human pre-embryo development is characterized by the induction of totipotency and then pluripotency. The understanding of this delicate process will have far reaching implication for in vitro fertilization and regenerative medicine. Human mature MII oocytes and embryonic stem (ES) cells are both able to achieve the feat of cell reprogramming towards pluripotency, either by somatic cell nuclear transfer or by cell fusion, respectively. Comparison of the transcriptome of these two cell types may highlight genes that are involved in pluripotency initiation.
Based on a microarray compendium of 205 samples, we compared the gene expression profile of mature MII oocytes and human ES cells (hESC) to that of somatic tissues. We identified a common oocyte/hESC gene expression profile, which included a strong cell cycle signature, genes associated with pluripotency such as LIN28 and TDGF1, a large chromatin remodelling network (TOP2A, DNMT3B, JARID2, SMARCA5, CBX1, CBX5), 18 different zinc finger transcription factors, including ZNF84, and several still poorly annotated genes such as KLHL7, MRS2, or the Selenophosphate synthetase 1 (SEPHS1). Interestingly, a large set of genes was also found to code for proteins involved in the ubiquitination and proteasome pathway. Upon hESC differentiation into embryoid bodies, the transcription of this pathway declined. In vitro, we observed a selective sensitivity of hESC to the inhibition of the activity of the proteasome.
These results shed light on the gene networks that are concurrently overexpressed by the two human cell types with somatic cell reprogramming properties.
Oocytes have the unique ability to remodel the chromatin of the germinal nuclei into a totipotent state. These modifications are particularly striking for the male pro-nuclei: upon fertilization, the sperm chromatin packaging protamines are stripped off and replaced by histones, the DNA is demethylated within 4 hours of fertilization, and the amino terminal tails of histones are modified including methylation of arginin 9 and phosphorylation of serin 10 of histone H3 (H3K9 and PhH3S10, respectively) [1, 2]. Remarkably, the reprogramming properties of oocytes are not restricted to the very specialized germinal nuclei. Indisputably, the cloning of Dolly has shown that the oocyte cytoplasm is able to extensively reverse the chromatin modifications associated with a differentiated state [3, 4]. Somatic cell nuclear transplantation (SCNT) has since been extended to other species, including human cells, and to many cell types, including terminally differentiated cells such as granulocytes [5, 6]. Thus differentiation is not anymore considered as an irreversible process, but rather as modifications of the cellular epigenome and transcriptome, that are amenable to complete reversal. In addition to oocytes, other cell types can reprogram somatic cells towards pluripotency. For example, using cell fusion strategies, it has been shown that hybrid cell clones obtained by fusion of a differentiated cell with either teratocarcinoma cells or embryonic stem cells display features of pluripotent, undifferentiated cells with concomitant loss of the markers associated with differentiation [7, 8]. More recently, and quite unexpectedly, Takahashi and Yamanaka have shown that the expression of only four selected transcription factors, OCT3/4, SOX2, CMYC and KLF4, is sufficient to drive a mouse fibroblast into an induced pluripotent stem cell (iPS) with all the features of embryonic stem cells, including a high growth rate and the ability to form a variety of tissues from all three germ layers in vitro and in vivo . These results have been confirmed by other studies, extended to human cells, and applied to non-fibroblastic cells such as mesenchymal stem cells (MSCs), gastric epithelial cells or hepatocytes [10–12]. At the center of cellular reprogramming lies the activation of the pluripotency transcriptional regulatory circuitry involving POU5F1/OCT4, NANOG and SOX2  and extensive chromatin-remodeling. However, the details of this process, such as the exact mediators of the chromatin modifications, remain ill defined. Data from xenopus egg experiments point to nucleosomal ATPases, but these findings await confirmation using mammalian oocytes [14, 15].
As oocytes and ES cells are two cell types able to reprogram a somatic cell such as fibroblasts into pluripotent cells, the comparison of the gene expression program of these two cell types could contribute to the understanding of these cell reprogramming properties. Therefore, we generated a transcriptome compendium of 205 samples by collecting public microarray data and compared the gene expression profile of oocytes and hESC to that of somatic tissues. We defined a common oocyte/hESC signature, which comprised many cell cycle genes, but also several biological pathways not associated with cell growth. Strikingly, a large set of genes is coding for genes involved in protein ubiquitination and the proteasome pathway. Upon hESC differentiation into embryoid bodies, the transcription of this pathway declines. In agreement with this preferential expression in pluripotent cells, we observed a selective sensitivity of hESC to the pharmacological inhibition of the proteasome activity, suggesting a role for this machinery in the maintenance of pluripotency.
Human oocytes and hESC share a common transcriptome signature
Samples of the microarray compendium
Tissue or cell line
Normal or Malignant
Number of samples
Normal cell compendium (n = 205)
Human embryonic stem cells
Central nervous system
Peripheral nervous system
Skin and keratinocytes
Tissue and cultured primary cells
Kidney and prostate
Heart and muscle
Tissue and purified cells
Highly cycling cells compendium (n = 22)
Leukemia cell lines
Lymphoma cell lines
Early erythroid cells
Cultured primary cells
Cultured primary cells
Hepatocarcinoma cell line
Colorectal cancer cell line
Breast cancer cell line
A strong cell cycle signature
Human oocytes and hESC share a large chromatin remodelling network
We focused the second part of our analysis on the non-cell cycle part of the oocyte/hESC signature. Removing the 220 cell cycles PS led to the definition of a "non-cell cycle oocyte/hESC signature" that retained 432 PS (384 transcripts). This signature contained many transcripts involved in DNA and histone modifications. One of these transcripts was DNMT3B, involved in DNA methylation. The high fold change of DNMT3B in hESC and oocytes compared to somatic samples (43.4 and 9.4, respectively) suggests a central role of this DNA methyltransferase in the control of the epigenome of these cells. In addition, several transcripts, comprising JARID2, SMARCA5, CBX5, CHAF1A and CBX1, were involved in histone modification processes (Figure 2C). We selected two chromatin remodelling genes, DNMT3B and SMARCA5, and validated by QRT-PCR their preferential expression in oocytes and hESC compared to somatic samples (Figure 2D).
Zinc finger genes
Genes from the mature oocyte/hESC signature with a Zinc finger domain.
Fold change Oocyte MII (a)
Fold change hESC (b)
D4, zinc and double PHD fingers family 2
GATA zinc finger domain containing 2A
Similar to Zinc finger protein 418
ring finger and CHY zinc finger domain containing 1
zinc finger CCCH-type containing 13
zinc finger CCCH-type containing 15
zinc finger, CCHC domain containing 8
zinc finger, AN1-type domain 6
zinc finger, MYM-type 2
zinc finger protein 131
zinc finger protein 281
zinc finger protein 3
zinc finger protein 330
zinc finger protein 508
zinc finger protein 588
zinc finger protein 84
zinc finger protein 93
zinc finger, ZZ-type containing 3
Ubiquitination and proteasome
High sensitivity of human embryonic stem cells to proteasome inhibition
Early human embryo development results in the reprogramming of highly specialized germinal cells into totipotent and then pluripotent cells that are the progenitors of all the specialized cell types of the human body. This unique biological property has been harnessed to restore pluripotency in human somatic cells by SCNT or cell-fusion using embryonic stem cells [6, 7]. hESC share with pluripotent stem cells from the inner cell mass pluripotency transcription factors and multi-lineage differentiation properties, and are considered a good in vitro model for pre-embryo pluripotent stem cells. Though human oocytes and ESC are developmentally separated by less than one week, the transcriptome of the oocyte undergoes rapid changes after fertilization [24, 25]. We undertook to find out a common expression signature to these two cell types, that share somatic cell reprogramming properties, by comparing them to a large collection of somatic tissues samples. A first observation was that the oocytes/hESC signature was highly enriched in genes involved in cell cycle. Whereas this was expected because of the cell cycle status of these two cell types, the expression of a large set of genes associated with cell division is nevertheless of interest for cellular reprogramming. As recently reported, prior mitotic remodeling of the somatic nuclei, involving topoisomerase II (TOP2)-dependent shortening of chromatin loop domains and an increased recruitment of replication initiation factors onto chromatin, is essential for reprogramming of differentiated nuclei . Strikingly, we found that TOP2A was highly up-regulated in both oocytes and hESC. This observation suggests that TOP2A could be a major factor in the reprogramming properties of oocytes and hESC by participating in chromatin remodeling. Conversely, the identification of a "cell cycle signature", shared with highly proliferating tissues such as cancer cell lines, provided a mean to identify by subtraction a "non-cycle oocytes/hESC" signature of 432 PS. This signature included transcripts coding for proteins involved in chromatin structure modifications such as DNMT3B, JARID2, SMARCA5 or CBX5 that contribute to the DNA methylation and chromatin remodeling (Figure 2C). Consistent with these observations, hESC display a distinct, permissive, chromatin structure compared with other tissues . Expression of DNA methyl-transferases or several ATP-dependent chromatin remodelling factors are elevated in murine oocytes or ES cells [28, 29]. Thus our findings show large similarities between murine and human ES cells, and put forward several genes whose strong overexpression could contribute to the specific chromatin state of hESC.
Another lesson from our transcriptomic approach is that the common oocytes/hESC gene expression profile has a very low number of genes that are either secreted or membrane bound (Figure 2A). This is in line with our previously published data that booth oocytes and hESC "specific genes" are significantly depleted in extracellular signalling components, suggesting that this feature is indeed a common characteristic shared by oocytes and hESC and is not simply due to a lack of overlap [18, 20]. Hence, genes specifically shared by oocytes and hESC are largely nuclear proteins. One assumption that can be inferred from these findings is that determinant of pluripotency may be mostly intrinsic factors. This observation converges on a recent model, which proposed that pluripotency is a ground state that is intrinsically self-maintained when protected from extrinsic differentiation stimuli .
An unexpected observation was that genes involved in protein ubiquitination and proteasome pathway were also overrepresented in the oocytes/hESC signature. This could be linked to the strong proliferation signature of hESC and oocytes as this pathway is by many way implicated in the regulating the cell cycle . However, the overexpression of the ubiquitination/proteasome pathway was still significant when the cell cycle signature was substracted, suggesting that this pathway could have a role in pluripotent cells in addition to its house keeping or cell cycle functions. In line with these results, we showed a selective sensitivity of hESC to the inhibition of the activity of the proteasome, resulting in loss of pluripotency and cell growth at doses without any detectable effects on differentiated but cycling cells such as primary fibroblasts or hESC derived fibroblast like cells. In addition, it must be stressed that the dramatic effects on hESC pluripotency were observed at doses of the proteasome inhibitor MG132 (0.5 μM) significantly lower than those typically found in the literature (several μM) or in mice ES cells (20 μM) . This observation is highly interesting in light of the recent findings of the role of the proteasome in transcription, especially in hESC. The 26S proteasome consists of a 20S core proteolytic part, capped by a 19S regulatory complex. Specificity of degradation of proteins is mediated in part by poly-ubiquitination of the substrate bound for destruction. Based on early work in yeast, the proteasome is known to interact with chromatin and function at multiple steps in transcription, both through proteolytic and non-proteolytic activities . Recently, Szutorisz et al. reported that the 26S proteasome is assembled on intergenic and intragenic regions in ES cells and act as a transcriptional silencer by blocking non-specific transcription initiation . This mechanism involves the proteolytic activity of the 20S core by degrading non-specific preinitiation complexes, thereby preventing permissive transcription and spreading of the modified chromatin. Our results are consistent with this hypothesis, but final answer on this issue will require further investigations.
This work has compared human MII oocytes and hESC to somatic tissues gene expression profiles. One goal was to provide new hints on the process of nucleus reprogramming which takes place in vivo during early embryo development or in vitro during SCNT, and may thus help to improve the iPS technology. Indeed, since the seminal work of the team of Shinya Yamanaka, numerous improvement have been made, including the identification of new genes able to replace some of the original ones in the reprogramming cocktail, the use of small molecules or the replacement of the retroviral vectors by adenoviruses or plasmids [33–37]. A first observation is that human mature oocytes do not express the pluripotency core transcriptional genes POU5F1/OCT4, NANOG and SOX2 , except POU5F1/OCT4 at low level (see Figure 1C and our Amazonia! on-line expression atlas, http://amazonia.montp.inserm.fr). They neither express KLF4 nor CMYC, which compose, with POU5F1/OCT4 and SOX2, the four factors that can reprogram somatic cells by virus-mediated overexpression . From the six "reprogramming" factors described to date, only LIN28 was found in the oocyte/hESC signature. However, POU5F1/OCT4, NANOG, SOX2, KLF4, LIN28 and CMYC are all expressed by hESC. Therefore, during early embryo development, the expression of these genes is induced. Thus, two different molecular pathways that can reprogram adult somatic cells can be envisioned: (i) the process taking place in the oocyte cytoplasm, able to activate the core transcriptional genes, or (ii) the overexpression of the core transcriptional genes themselves together with adjuvant genes, either by viral overexpression or by fusion with cells already expressing these genes. It can be speculated that the factors that lie upstream of the pluripotency core transcriptional circuitry are expressed as mRNA in mature MII oocytes and are still present at blastocyst stage from which hESC are derived. Thus, the oocytes/hESC signature likely includes these factors, and therefore this information could be highly informative for cell reprogramming. The signature contained numerous transcritption factors, including many zinc finger such as ZNF84, several still poorly annotated genes such as KLHL7, MRS2, or the Selenophosphate synthetase 1 (SEPHS1), displayed a strong cell cycle signature, chromatin modification genes, and also many actors of the proteasome pathway. All these genes are candidate genes to improve the efficiency of iPS generation, especially in the light of the recent advances that uses non retroviral vectors but at the cost of lower efficacy.
Human ESC are not only a very promising source of cells for regenerative medicine, but are also a unique tool to understand early embryo development that can not easily be studied on live embryos because of ethical and technical limits. Our comparison of human mature oocytes and hESC to a large collection of somatic samples helps to understand the early embryo development and pluripotency, and is therefore relevant for therapeutics, including improvement of the pregnancy success rate in IVF and regenerative medicine applications such as those involving cell reprogramming.
We built an expression compendium by combining U133A and U133 Plus 2.0 (Affymetrix, Santa Clara, USA) microarray data from 11 publications and from our laboratory, totalizing 205 samples (Table 1; see Additional file 1) [18, 38–47]. Data were analyzed with the GCOS 1.2 software (Affymetrix), using the default analysis settings and global scaling as first normalization method, with a trimmed mean target intensity value (TGT) of each array arbitrarily set to 100. Data was floored at 50, i.e each value below 50 was set to 50. In order to compare U133A and U133 Plus 2.0 data, we further normalized the data with a rank-based normalization method. This method, "MetaNorm", orders the values of the 22 215 PS of the Affymetrix U133A microarray and allocates a new value to each PS according to its rank, using a unique signal value template (Assou et al., manuscript in preparation). Samples are listed in Table 1 (see Additional file 1), along with references, microarray design and, when available, GEO (Gene Expression Omnibus) dataset number. The dataset is available as Additional file 2 (signal and p-value) and each PS can be individually accessed on our website http://amazonia.montp.inserm.fr.
Data analysis and visualization
Principle component analysis (PCA) was performed using ArrayAssist® software (Stratagene, La Jolla, CA, USA) to provide a global view of how the various sample groups were related. Hierarchical clustering was carried out with CLUSTER and TREEVIEW software . PCA and clustering were performed on 10,000 PS with the highest coefficient of variation (CV). Gene expression profiles were identified using two-class Significance Analysis of Microarrays (SAM) method http://www-stat.stanford.edu/~tibs/SAM/ which utilizes a Wilcoxon-test statistic and sample-label permutations to evaluate statistical significance. SAM analysis was applied after data filtering retaining only PS with at least 2 samples with a "Present" call. The False Discovery Rate (FDR), an estimate of the fraction of selective genes, was kept below 5% in all statistical analyses. Gene Ontology annotation analysis was carried out using the Fatigo+ tool at the Babelomics website http://babelomics.bioinfo.cipf.es. Only annotations with a false discovery rate-adjusted P-value below 0.05 were considered significant. To uncover functional biological networks, we imported gene expression signatures into the Ingenuity Pathways Analysis (IPA) Software (Ingenuity Systems, Redwood City, CA, USA). Comparison of the frequency of zinc finger domain containing transcript between the non-cell cycle oocytes/hESC signature and the entire U133A microarray was carried out using a Pearson's Chi-squared test with Yates' continuity correction.
Human mature MII oocytes, fibroblasts and malignant cell lines transcriptome
Unfertilized MII oocytes were collected after informed consent 44 hours post insemination or post microinjection by ICSI as previously published [18, 44]. Briefly, Mll oocytes were from couples referred to our center for cIVF (tubal infertility) or for ICSI (male infertility). Mature M2 oocytes were pooled: 16 oocytes for Oocyte_M2_16 sample, 21 for Oocyte_M2_21 and 24 for Oocyte_M2_24, from 6, 8 and 8 patients respectively. Human foreskin fibroblasts cell lines were described previously . MCF7 and HEPG2 were from ATCC and cultured in DMEM medium containing 10% fetal calf serum (FCS). Total RNA was isolated using RNeasy mini kits (Qiagen, Courtaboeuf, France) and quantified using a NanoDrop spectrophotometer (Thermo Fischer, Wilmington, Delaware, USA). Total RNA (100 ng) was used to prepare twice amplified labeled cRNA for hybridization to HG-U133 plus 2.0 GeneChip pangenomic oligonucleotide arrays (Affymetrix, Santa Clara, CA, USA) as previously described . The 9 microarray data obtained in our lab are accessible in US National Center for Biotechnology Information, Gene Expression Omnibus (GEO) through the provisional accession numbers GSE11450 (series), and GSM288886, GSM288885, GSM288883, GSM288882, GSM288880, GSM288878, GSM288877, GSM288876, GSM288812 (samples).
hES cell culture
The HS181 hES cell line was imported from the Karolinska Institute (Stockholm, Sweden). The HD83/D17/FE07-135-L1 and HD90/D18/FE07-142-L1 hES cell lines were derived in our laboratory from a normal embryo and an embryo that carried an abnormal VHL gene according to preimplantation genetic diagnostic, respectively (De Vos et al. manuscript in preparation). Briefly, derivation of HD83 and HD90 was carried out using mechanical dissociation of the inner cell mass . The culture medium used for hESCs derivation and culture consisted of 80% KO-DMEM, 20% knockout SR, 2 mM L-glutamine, 1% nonessential amino acids, 0.5 mM β-mercaptoethanol (all from Gibco Invitrogen, Cergy-Pontoise, France) and 10 ng/mL of bFGF (Abcys, Paris, France). Passaging was performed mechanically by cutting the colony using a #15 scalpel under the microscope. Human foreskin fibroblasts (HFF), mitotically inactivated using irradiation (40 Gy), were used as feeder cells. HFF cells were cultured in 85% DMEM, 15% FBS. All hESC expressed POU5F1/OCT4, NANOG and TRA-1-60, and were able to differentiate into embryoid bodies that expressed differentiation markers. For proteasome inhibition experiments, hESC were incubated 40 h with various concentration of MG132 (Sigma), with medium renewal at 24 h.
Production of hES-derived fibroblasts
Briefly, hES cells were mechanically isolated and plated on laminin precoated 6-wells culture dishes (Becton Dickinson, San Jose, CA, USA) in hESC culture medium renewed every day. After 5 days, bFGF was removed, and after three additional days, medium was switched to HFF medium. In these conditions, hES cells differentiated into flattened cells with elongated nucleus and branching pseudopodia forming hESC-derived fibroblasts (hES-dF). The hES-dF were then mechanically isolated and transferred to feeder free 6-wells culture dishes. Subsequent passages were carried out using 0.05% trypsin- EDTA (Invitrogen) every 6 days and cultures upscaled into T75 flasks.
RT-PCR and quantitative PCR (QRT-PCR)
Primer sequences and conditions used for RT-PCR
Primer sequences (Forward, Reverse)
Annealing Tm (°C)
Product size (bp)
R: CTGGATGTTCTGG GTCTGGT
Immunofluorescence and cytometry flow
Cells were fixed with PBS containing 4% paraformaldehyde for 20 minutes at room temperature and blocked with PBS containing 5% normal donkey serum for 30 minutes at room temperature. After blocking, cells were incubated with the appropriate primary antibody against POU5F1/OCT4 (sc-9081, Santa Cruz Biotechnology, Santa Cruz, CA; 1:300) or against proline 4-hybroxylase (P4H) (Dako, Trappes, France; 1:50) for 1 hour at room temperature. Cells were washed three times in PBS and incubated for 1 hour at room temperature with Alexa Fluor® 488 donkey anti-Rabbit (A-11034; Molecular Probes; 1:1000) and Alexa Fluor® 568 goat anti-mouse antibody (A11019, Invitrogen; 1:400) secondary antibodies for POU5F1/OCT4 and P4H respectively. Hoechst staining was added to first wash (Sigma, 5 μg/ml).
For flow cytometry, cells were harvested by treatment with 0.05% trypsin- EDTA (Invitrogen) and were resuspended in culture media. Cell aliquots were incubated on ice with anti-CD13 MAb conjugated to phycoerythrin (PE) (A07762, Beckman-Coulter, 1:50), anti-CD44 MAb conjugated to fluorescein isothiocyanate (FITC) (clone J-173, Immunotech; 1:50) and Tra-1-60 (90232, Chemicon) or conjugated isotypic controls. Flow cytometry was performed on a fluorescence-activated cell sorter (FACS Scan, Becton Dickinson), and data were analyzed with the Cellquest software (Becton Dickinson).
We are grateful to the various labs that gave free access to their complete transcriptome data, in agreement with the MIAME recommendations . We thank Isabelle Rodde-Astier and Bruno Delorme (MacoPharma) for their support, Laure Nadal for excellent technical work, Marc Piechaczyc et Isabelle Jariel for helpful discussions on the proteasome and for providing reagents and Marilyne Dijon for critical reviewing of the manuscript. Supported by the University Hospital of Montpellier, the Association Française contre les Myopathies (AFM), Ferring and Organon phamaceuticals compagnies.
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