Cell-type phylogenetics and the origin of endometrial stromal cells.
A challenge of genome annotation is the identification of genes performing specific biological functions. Here, we propose a phylogenetic approach that utilizes RNA-seq data to infer the historical relationships among cell types and to trace the pattern of gene-expression changes on the tree. The hypothesis is that gene-expression changes coincidental with the origin of a cell type will be important for the function of the derived cell type. We apply this approach to the endometrial stromal cells (ESCs), which are critical for the initiation and maintenance of pregnancy. Our approach identified well-known regulators of ESCs, PGR and FOXO1, as well as genes not yet implicated in female fertility, including GATA2 and TFAP2C. Knockdown analysis confirmed that they are essential for ESC differentiation. We conclude that phylogenetic analysis of cell transcriptomes is a powerful tool for discovery of genes performing cell-type-specific functions.
Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT 06511, USA; Yale Systems Biology Institute, Yale University, New Haven, CT 06516, USA.
Koryu
K
Kin
Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT 06511, USA; Yale Systems Biology Institute, Yale University, New Haven, CT 06516, USA.
Mauris C
MC
Nnamani
Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT 06511, USA; Yale Systems Biology Institute, Yale University, New Haven, CT 06516, USA; Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.
Vincent J
VJ
Lynch
Department of Surgery, Yale University, New Haven, CT 06519, USA.
Elias
E
Michaelides
Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT 06511, USA; Yale Systems Biology Institute, Yale University, New Haven, CT 06516, USA. Electronic address: gunter.wagner@yale.edu.
Günter P
GP
Wagner
D002454:Cell Differentiation; D002460:Cell Line; D016000:Cluster Analysis; D004717:Endometrium / Q000166:cytology*; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D050989:GATA2 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D058628:Myofibroblasts / Q000166:cytology / Q000378:metabolism; D011247:Pregnancy; D025341:Principal Component Analysis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017423:Sequence Analysis, RNA; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism*; D050656:Transcription Factor AP-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; D034741:RNA, Small Interfering; C493679:TFAP2C protein, human; D050656:Transcription Factor AP-2