title: Research resource: interactome of human embryo implantation: identification of gene expression pathways, regulation, and integrated regulatory networks.
abstract: A prerequisite for successful embryo implantation is adequate preparation of receptive endometrium and the establishment and maintenance of a viable embryo. The success of implantation further relies upon a two-way dialogue between the embryo and uterus. However, molecular bases of these preimplantation and implantation processes in humans are not well known. We performed genome expression analyses of human embryos (n = 128) and human endometria (n = 8). We integrated these data with protein-protein interactions in order to identify molecular networks within the endometrium and the embryo, and potential embryo-endometrium interactions at the time of implantation. For that, we applied a novel network profiling algorithm HyperModules, which combines topological module identification and functional enrichment analysis. We found a major wave of transcriptional down-regulation in preimplantation embryos. In receptive-stage endometrium, several genes and signaling pathways were identified, including JAK-STAT signaling and inflammatory pathways. The main curated embryo-endometrium interaction network highlighted the importance of cell adhesion molecules in the implantation process. We also identified cytokine-cytokine receptor interactions involved in implantation, where osteopontin (SPP1), leukemia inhibitory factor (LIF) and leptin (LEP) pathways were intertwining. Further, we identified a number of novel players in human embryo-endometrium interactions, such as apolipoprotein D (APOD), endothelin 1 (END1), fibroblast growth factor 7 (FGF7), gastrin (GAST), kringle containing trnasmembrane protein 1 (KREMEN1), neuropilin 1 (NRP1), serpin peptidase inhibitor clade A member 3 (SERPINA3), versican (VCAN), and others. Our findings provide a fundamental resource for better understanding of the genetic network that leads to successful embryo implantation. We demonstrate the first systems biology approach into the complex molecular network of the implantation process in humans.
authors.affiliation: Department of Clinical Science Intervention, and Technology, Division of Obstetrics and Gynaecology, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden. signe.altmae@ut.ee
authors.forename: Signe
authors.initials: S
authors.lastname: Altmäe
authors.forename: Jüri
authors.initials: J
authors.lastname: Reimand
authors.forename: Outi
authors.initials: O
authors.lastname: Hovatta
authors.forename: Pu
authors.initials: P
authors.lastname: Zhang
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.forename: Triin
authors.initials: T
authors.lastname: Laisk
authors.forename: Merli
authors.initials: M
authors.lastname: Saare
authors.forename: Maire
authors.initials: M
authors.lastname: Peters
authors.forename: Jaak
authors.initials: J
authors.lastname: Vilo
authors.forename: Anneli
authors.initials: A
authors.lastname: Stavreus-Evers
authors.forename: Andres
authors.initials: A
authors.lastname: Salumets
mesh_terms: D053399:Apolipoproteins D / Q000378:metabolism; D001755:Blastocyst / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D046149:Embryo Culture Techniques; D010064:Embryo Implantation / Q000235:genetics; D004717:Endometrium / Q000502:physiology*; D019332:Endothelin-1 / Q000378:metabolism; D005260:Female; D051523:Fibroblast Growth Factor 7 / Q000378:metabolism; D005755:Gastrins / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism; D020738:Leptin / Q000378:metabolism; D053605:Leukemia Inhibitory Factor / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D039942:Neuropilin-1 / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D025941:Protein Interaction Mapping; D050791:STAT Transcription Factors / Q000378:metabolism; D015843:Serpins / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D053675:Versicans / Q000378:metabolism
chemical_list: D053399:Apolipoproteins D; D015815:Cell Adhesion Molecules; D019332:Endothelin-1; D005755:Gastrins; C486075:KREMEN1 protein, human; D020738:Leptin; D053605:Leukemia Inhibitory Factor; D008565:Membrane Proteins; C516148:SERPINA3 protein, human; D050791:STAT Transcription Factors; D015843:Serpins; D051523:Fibroblast Growth Factor 7; D053675:Versicans; D039942:Neuropilin-1; D053612:Janus Kinases
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