Briefings in Functional Genomics Advance Access published online on July 31, 2007
Briefings in Functional Genomics, doi:10.1093/bfgp/elm012
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Functional genomics of human pre-implantation development
Corresponding author. James Adjaye, Max Planck Institute for Molecular Genetics, Molecular Embryology and Aging Group, Department of Vertebrate Genomics, Ihnestrasse 73, D-14195 Berlin, Germany. Tel: 0049-30-8413-1203; Fax: 0049-30-8413-1128; E-mail: adjaye{at}molgen.mpg.de
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ABSTRACT |
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ABSTRACT
INTRODUCTIONEarly mammalian embryogenesis is currently the focus of intense interest because of the potential of inner cell mass-derived embryonic stem cell lines in new therapeutic strategies. As such, creating molecular profiles of gene expression during pre-implantation development will provide a framework for understanding the biological properties of these cells and also establish a tool set for subsequent functional studies. However, a major obstacle impeding progress in this area are moral issues regarding their use, the scarcity of these cells and the ability to successfully isolate and amplify enough mRNA from the minute amounts of total RNA present in these cells. The elucidation, unravelling and understanding the molecular basis of transcriptional control during pre-implantation development is of utmost importance if we are to diagnose, intervene, eliminate or reduce abnormalities associated with growth, disease and infertility by applying assisted reproduction. Importantly, these studies should enhance our knowledge of basic reproductive biology and its application to regenerative medicine.
This review describes the application of in silico-based approaches, in order to obtain maximal information from published microarray-based gene expression data. For an illustration of this, we used gene expression data related to unfertilized oocytes and blastocysts to gain insights into genes and related signalling pathways (e.g. MAPK, PI3K, WNT, TGF-ß) involved in the switch from maternal to embryonic control of gene transcription during human pre-implantation development.
Keywords: Human, pre-implantation development, gene expression, oocytes, blastocysts, microarrays, bioinformatics, functional genomics, signalling pathways
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INTRODUCTION |
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During early embryogenesis maternal proteins control the developmental programme until embryonic genome activation takes place. Maternal effect genes important to these early stages of development have been well documented in Caenorhabditis elegans, Drosophila melanogaster and Xenopus laevis [1–3], but their presence has only been inferred in mammals [4, 5]. During the transition from maternal to embryonic control of development, maternal transcripts (common to both the unfertilized oocyte and early embryo) are depleted and embryo-specific transcripts involved in early embryogenesis are generated. In addition, protein synthesis is required for embryonic genome activation, which occurs at the 2-cell stage in mice and between the 4- and 8-cell stages in humans [6]. This is consistent with a need to synthesize essential transcription factors and other regulatory proteins lacking in the oocyte as has been shown in the mouse [7–9]. Genome-wide demethylation which is related to the expression of a gene is reported to occur frequently during mouse pre-implantation development between the 8-cell and blastocyst stages [10]. Furthermore, the poly (A) content per mouse embryo also increases 5-fold from the 2-cell to the blastocyst stage [11]. These lines of evidence suggest that many genes are turned on during this developmental cascade.
Key developmental events occur in the embryo before implantation, resulting in changes in cell shape at compaction of the 8-cell embryo and segregation of cells to the ICM (inner cell mass) and the TE (trophectoderm) of the blastocyst. These cell lineages differ in morphology, function and developmental fate. At the 2-cell, 4-cell and 8-cell stages, single blastomeres are totipotent and can therefore develop into a complex organism containing all types of specialized somatic cells. The ICM of the blastocyst and primordial germ cells of fetal stages lose such totipotency and become pluripotent, thus indicating gradual restriction of the developmental potency of these cells [12]. In the fully expanded blastocyst, the ICM is initially a non-differentiated, proliferating stem cell population with the capacity to form all the tissues of the fetus. The TE cells are typically epithelial and following proliferation, form extra-embryonic structures such as the placenta. Inner cell mass and TE cells isolated from human blastocysts express common but also distinct genes [13] and, synthesize different proteins [14]. It is, therefore, clear that differential gene expression underlies the delineation of these two cell types, and therefore reasonable to hypothesize that many kinds of differentiation-related genes [15, 16] are present in the blastocyst [13]. This suggests that these changes in gene expression between the two lineages are associated with the commitment to differentiate into different cell types.
Amongst the genes studied extensively in relation to stem cell self-renewal is OCT4/Oct4, a transcription factor expressed throughout mouse and human pre-implantation development [15, 17–19], but later becomes restricted to inner cell mass cells and epiblast derivatives [13, 20]. This expression pattern is consistent with a dual role of OCT4/Oct4 in maintaining the pluripotency of ICM and embryonic stem cells in human and mouse [13, 15, 21], and in preventing the expression of genes that are required for differentiation of embryonic stem cells.
Despite the fundamental importance of the transition from maternal to embryo-encoded gene transcription, and the observed morphological changes in the developmental programme, progress in understanding how pre-implantation embryonic cells establish regulation of transcription and their own pattern of gene expression from a completely inactive genome has been hampered by the lack of molecules known to regulate these processes. So far, detailed studies of gene expression in pre-implantation human embryonic cells have been limited to previously characterized genes using such methods as reverse transcription-polymerase chain reaction (RT-PCR) amplification with known primer sequences. Such analyses have been hampered by the scarcity and small size of human embryos and there has been little opportunity to screen for the many human gene sequences that are rapidly becoming available through the human genome sequencing project and the various EST (expressed sequence tags) databases. Another limitation to these approaches is that only known sequences can be analysed, thus, genes expressed specifically during human pre-implantation development remain unidentified. To overcome these limitations, a reproducible technique was developed for generating pools of cDNA libraries from single embryonic cells and a limited number of primordial germ cells [18, 22].
As an application, single cell RT-PCR analysis on lysed cells has proved useful in examining gene expression in single human embryos [23–30]. However, these approaches are limited by the number of genes that can be analysed in each individual embryo. For mammals, the amounts of maternal RNA in oocytes are in the range of 0.47 ng/oocyte (mouse) to 0.98 ng/oocyte (cow) [31]. The number of cells in a blastocyst is approximately 150. Since the total RNA content of a single mammalian cell is in the range of 20–40 pg and only 0.5–1.5 pg of this is mRNA [32, 33], any attempt at single cell or embryo profiling must be capable of dealing with a total of 105–106 mRNA molecules, therefore cDNA or mRNA amplification is unavoidable if we are to attempt to examine all, or at least the majority of genes expressed in individual cells. For this purpose, a variety of global amplification protocols have been established. These include, messenger RNA isolation coupled to whole genome RT-PCR to generate large quantities of double-stranded cDNAs (uncloned libraries) from single embryos [18, 22, 28, 34–36]. However, there are significant limitations and shortcomings to cDNA and mRNA amplification technologies that should be kept in mind when designing studies that depend on these technologies. In both cases, the two main concerns are; the representation of all transcripts present in the starting material in the final amplified material (e.g. loss of transcripts) and the preservation of the relative abundances of the different transcripts. All of the available methods compromise these features to some degree.
Among the various gene expression detection methods which have also been applied to pre-implantation development in human are subtractive hybridization [37, 38], EST generation [18, 39], differential display [22, 37] serial analysis of gene expression—SAGE [40, 41], in situ data mining [42] and finally microarrays [13, 43–47]. Although each technique has its own unique merit, microarray technologies have gained precedence as they enable comparative whole-genome transcriptome analysis. In spite of this, there is a major drawback with the use of microarrays in comparison to other technologies, in that some low abundant oocyte- and embryo-specific transcripts may not be represented as probes on most microarray platforms. Additionally, deadenylated mRNAs which are known to be stored as inactive transcripts in oocytes would never be isolated or transcribed using oligo-dT-mediated mRNA labelling protocols, and therefore these genes within the oocyte pool will never be presented as labelled targets for possible detection on the arrays.
To date, most of the detailed microarray-based gene expression studies during pre-implantation development have been studied in the mouse [7–9, 48, 49] and have served to provide us with much of our knowledge of early mammalian development. However, there are differences between mammals and it is not always possible to extrapolate from other mammals to the human to establish molecular correlates of early human development. For example, differences in human and mouse embryonic expression patterns of developmental control genes such as WNT 7A/Wnt7a (significant differences in spatial and temporal expression patterns in the developing midbrain and telecephalon) and CAPN3/Capn3, the locus for LGMDA2A limb girdle muscular dystrophy (significant differences in embryonic heart, lens and smooth muscle) [50]. Also, the demonstration of biallelic expression of XIST/Xist in human and monoallelic expression in the mouse further highlights differences between mouse and human [51, 52]. Furthermore, even at early stages of development, phenotypic differences have been observed emanating from equivalent mutations in orthologous human and mouse genes [53]. Collectively, this evidence strongly supports the need to identify and functionally characterize human maternal and/or embryonic genes that might have roles in regulating these early developmental processes. Ultimately, research should be carried out in parallel with mouse and human samples to have a clearer and definitive picture of early mammalian development as has been demonstrated with the detailed expression of HOXD1/Hoxd1 during mouse and human development [34].
The limited availability and ethical issues regarding the acquisition and use of supernumerary human pre-implantation embryos for research purposes has meant that only a few laboratories with access to such material are able to conduct this type of research. This article reviews previously published microarray-based gene expression data pertaining to human oocytes and blastocysts and provides insights and know-how on approaches than can be used to maximize the information that can be gained from available data sets.
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THE USE OF MICROARRAY PLATFORMS AS A MEANS OF IDENTIFYING GENES AND RELATED SIGNALLING PATHWAYS OPERATIVE DURING HUMAN PRE-IMPLANTATION DEVELOPMENT |
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A detailed description on mRNA isolation, reverse transcription and whole-genome amplification, and detection of differential expression between, for example, human unfertilized oocytes and embryos at the 8-cell stage of development to investigate the molecular mechanisms underlying embryonic genome activation (EGA) has been described [13]. Additional microarray-based gene expression studies using human oocytes and pre-implantation stage embryos have been reported [13, 43–47]. Al1 these studies provide valuable information on the transcriptome of unfertilized oocytes, with the exception of [13], which focused on detailed transcriptional and related signalling and metabolic pathways operative in ICM and TE cells. The increased tendency of studying oocytes may be due to the convenience of obtaining these cells and also the limitation of gaining access to human pre-implantation embryos.
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ASSIMILATION OF MICROARRAY-BASED EXPRESSION DATA |
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A major effort has been made to set a standard on data presentation and exchange through the establishment of a universally acceptable format, namely, the minimum information about a microarray experiment—MIAME [54]. Despite this, most journals do not strictly adhere to this as a prerequisite for publications of array-based manuscripts and as such raw files pertaining to whole genome expression analyses of human pre-implantation embryos are not always available. This, therefore, makes it impossible for those without access to these rare cells but is, nonetheless, interested in carrying out detailed molecular analysis of human pre-implantation development. To circumvent this deficiency, we used published data sets [43, 45–47] to re-evaluate in more detail the molecular portraits of human oocytes and pre-implantation embryos. Another potential data set described by Bermudez et al. [44] only listed annotated genes and therefore of limited use for independent analysis of their data set.
Of the four publications we analysed, Dobson et al. [45] and Li et al. [47] used 4- and 8-cell stage embryos, in addition to unfertilized oocytes for their studies. Of these, Kocabas et al. [46], compared the transcriptome of human metaphase II oocytes with a reference sample consisting of a mixture of total RNA from 10 different normal human tissues not including the ovary. The Affymetrix Human Genome U133 Plus 2.0 GeneChip arrays were used for their analysis. They provided a complete data set of up- or down-regulated or unique genes in oocytes.
Dobson et al. [45], studied the global patterns of gene expression in oocytes (primary and secondary) and in individual, normal embryos during the first 3 days of embryonic life (day 1 embryos; pronuclei stage, day 2 embryos; 3- or 4-cells, day 3 embryos; 7- or 8-cells) using cDNA microarrays. A list of 1896 genes with at least a 4-fold change in expression (with <1% false discovery rate) was accessible for our analysis.
Li et al. [47] used a cDNA microarray containing 9600 probes to investigate differential gene expression in oocytes, 4-cell and 8-cell embryos. They provided lists of genes expressed more than 2-fold in these samples. There were 180 genes expressed in oocytes, out of which 155 were annotated and the rest were ESTs. We used the set of 155 genes for our analysis.
Assou et al. [43], analysed genome-wide gene expression in pooled immature and mature oocytes or cumulus cells employing an oligonucleotide-based microarray platform. They identified 1514 up-regulated genes in the oocytes relative to cumulus cells. Unfortunately, we could only access a list of 72 genes which was provided as supplementary data.
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GENE EXPRESSION IN UNFERTILIZED HUMAN OOCYTES |
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The study of genes and regulatory pathways active in oocytes may lead to a better understanding of basic reproductive biology and somatic cell nuclear transfer (SCNT) which may lead to solutions for infertility problems or improvements in assisted reproductive technologies (ARTs). Furthermore, these genomic-based studies may increase the meagre information available on human oogenesis, folliculogenesis, fertilization and embryonic development.
As the four publications we used for our analysis utilized oocytes, we combined these lists of genes as a representation of the transcriptome of an oocyte. To identify a common set of genes within these data sets, we performed a comparative analysis (Figure 1). Surprisingly, there were no genes common between all four data sets. Possible reasons that could account for this are;
- The complete data set from each of these publications were inaccessible. The number of genes available as expressed in oocytes were 3767, 177, 226 and 72 in Kocabas et al. [46], Li et al. [47], Dobson et al. [45] and Assou et al. [43], respectively.
- Different microarray platforms were used and therefore distinct algorithms for scoring expression.
- The oocytes used in the various studies were not homogenous with respect to maturity and quality.
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Due to the large data set available from Kocabas et al. [46] maximum overlap was found between this data set when compared to the others. The number of genes common between Kocabas et al. [46], and the other data sets [43, 45, 47] were 82, 23 and 60, respectively (Figure 1). Amongst these were well known oocyte marker genes identified by [46]. For example, ZP3 was in common with the list provided by Dobson et al. [45], BUB3 was present in Li et al. [47] (Figure 1A and C) and markers such as, ZP1, ZP2, ZP3, KIT, GDF9, DAZL, DNMT1, KIT, MOS were in common with Assou et al. [43] (Figure 1B and C). Minimal overlap was found in the comparisons between Li et al. [47] and Dobson et al. [45] (Figure 1A and D—IL13RA2), Assou et al. [43] and Dobson et al. [45] (Figure 1B and D—CENPA, ZP3) and, Assou et al. [43] and Li et al. [47] (Figure 1C and D—MCM3). The list of genes and associated Gene Ontologies pertaining to Figure 1 can be provided upon request.
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COMPARATIVE MOLECULAR PORTRAITS OF UNFERTILIZED OOCYTES AND BLASTOCYST |
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To identify putative genes expressed in both oocytes and blastocysts, oocytes only (maternal) and blastocyst only (embryonic), we compared our previously published microarray data set consisting of 5862 genes detected as expressed in human blastocysts [13] to the 4038 combined oocyte expressed genes [43, 45–47]. As can be seen in Figure 2, 894 genes were common to oocytes and blastocysts, 3144 as oocytes only (e.g. MOS, GDF9, ZP1, ZP2, ZP3, ZP4, KIT, DNMT1, H1FOO, BMP15), and 4968 as blastocyst only (e.g. TNK1, HMGB1, GLTSCR2, ITGA6, ATP1B3, RPL14). These blastocyst expressed genes maybe involved in the switch from maternal to embryonic control of transcription (MET/EGA) and those expressed as a consequence of this process, for example, ATP1B3, a Na+/K+-ATPase, is overexpressed in the TE, thus reflecting the roles played by these ATPases in driving transepithelial Na+ and fluid transport for blastocoel formation. We chose not to include the data sets on 4-cell and 8-cell embryos [45, 47] as these lists were incomplete and therefore of limited value to our analysis.
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GENE ONTOLOGY AND PREDICTION OF SIGNALLING PATHWAYS OPERATIVE IN OOCYTES AND PRE-IMPLANTATION EMBRYOS |
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To enable investigations of gene function and metabolic and signalling pathways crucial for executing successful oogenesis and pre-implantation development, gene expression data sets can be interrogated using available databases designed for this purpose. An example is the Gene Ontology (GO) database (http://www.geneontology.org), which consists of a systematic and standardized nomenclature for annotating genes in various organisms based on three main ontologies; molecular function, biological process and cellular component [55]. This together with other integrated web-accessible data mining tools is presented in Table 1.
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As an illustration, to identify common and distinct pathways operative during EGA, the oocyte and blastocyst list of genes served as input for the DAVID annotation tool [56] and FATIGO+ [57] pathway analysis tools. The results are presented in Tables 2–4
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We used both the annotation tools for our analysis because each has unique characteristics and features. FATIGO+ facilitates the viewing of pathways simultaneously for two different input lists, unlike DAVID, which was more accurate for our study. DAVID requires a separate submission of different gene lists. Interestingly, this analysis revealed the presence of some of the proven biologically significant pathways in oocytes and blastocysts, which were not shown to be significant employing the FATIGO+ analysis tool for the same gene list. Surprisingly, some of the known pathways e.g. the Phosphatidylinositol (PI3K/Akt) pathway known to be operative in mouse and human blastocysts [13, 58] were also not shown to be significant using the DAVID analysis tool. In essence, it is advisable to implement both tools when analysing genes and their related pathways.
The TGF-ß pathway (Figure 3), MAP kinase (Figure 4) and PI3K/Akt signal transduction (Figure 5), are well known pathways operative during mammalian pre-implantation development and in embryonic stem cells [13, 58]. Riley et al. [58] found that the p85 and p110 subunits of PI3K and Akt are expressed from the 1-cell through the blastocyst stage of murine pre-implantation development. Furthermore, inhibition of Akt activity had significant effects on the normal physiology of the blastocyst and also resulted in a delay in blastocyst hatching, a developmental step facilitating implantation. Maekawa et al. [59] showed that inhibition of the JNK pathway or of the p38 MAP kinase pathway, but not of the ERK pathway, results in inhibition of cavity formation, and that JNK and p38 are active during mouse pre-implantation development. Kocabas et al. [46] confirmed the presence of TGF-ß pathway in human oocytes, previously described in mouse [60].
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To facilitate further analysis of genes of interests, we have presented three web-based databases (Table 1) for interrogating genes expressed in blastocysts under various experimental conditions and their corresponding Gene Ontologies viz;
- Primary differentiation in the human blastocyst: comparative molecular portraits of inner cell mass and TE cells. [13].
- Analysis of OCT4 dependent transcriptional networks regulating self-renewal and pluripotency in human embryonic stem cells [15].
- Conserved molecular portraits of bovine and human blastocysts as a consequence of the transition from maternal to embryonic control of gene expression during pre-implantation development [61].
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CROSS-SPECIES COMPARATIVE GENOMIC ANALYSIS USING MICROARRAYS |
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Microarray-based gene expression analysis in human is indeed lagging in comparison to the mouse. An alternative potential solution to this problem is the use of cross-species hybridizations, i.e. human sequence-based arrays as tools for undertaking comparative genome expression studies using RNA derived from other species such as bovine [62]. Using this approach [61], we investigated conserved mRNA expression profiles of bovine and human oocytes and blastocysts employing an array consisting of 15 529 human cDNAs as probe which is the same platform used for the blastocyst study [13]. The analysis revealed 419 genes conserved in both, oocytes and blastocysts, with 1324 genes detected exclusively in the blastocyst, in contrast to 164 in the oocyte. These included a significant number of novel genes. Genes indicative for transcriptional and translational control (ELAVL4, TACC3) were overexpressed in the oocyte, whereas cellular trafficking (SLC2A14, SLC1A3), proteasome (PSMA1, PSMB3), cell cycle (CCNE1, GSPT1), protein modifications and turnover (TNK1, UBE3A) were found to be overexpressed in blastocysts. Transcripts implicated in chromatin remodelling were found in both oocytes (NASP SMARCA2, DNMT1) and blastocysts (H2AFY, HDAC7A).
To enable a global overview of conserved gene expression in oocytes and blastocysts, which can be interrogated, we have presented the expression data as a database for searching the expression levels of specific genes and their related Gene Ontologies (http://goblet.molgen.mpg.de/cgi-bin/stemcell/preimplantation-development.cgi) (Table 1).
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CONCLUDING REMARKS |
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We hope our analysis of gene expression patterns employing microarray-based approaches has demonstrated how one gains insights into gene regulatory networks operative in human oocytes and blastocysts. Such an undertaking would be a major step forward in unravelling molecular mechanisms associated with developmental abnormalities resulting from in vitro manipulation and culture of embryos for assisted reproduction. In addition, embryo-related technologies, such as in vitro production of embryos for stem cell derivation and somatic nuclear transfer, can only be successfully and reproducibly achieved once we have a clearer understanding of the molecular mechanisms underlying pre-implantation development. Most importantly, our increased knowledge of genes and related transcriptional networks operative during oogenesis and embryogenesis should lead to advances in assisted reproduction and pre-implantation genetic diagnosis (PGD) in human.
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Funding |
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This work was supported by the Max Planck Society and the DFG (AD 184/5-1).
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Acknowledgements |
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We are grateful to Prof. Hans Lehrach for his support.
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FOOTNOTES |
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Smita Sudheer is a PhD student working on gene expression during mammalian pre-implantation development.
James Adjaye is Group Leader of the Molecular Embryology and Aging Group at the Max Planck Institute for Molecular Genetics.
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