The androgen and progesterone receptors regulate distinct gene networks and cellular functions in decidualizing endometrium.
Progesterone is indispensable for differentiation of human endometrial stromal cells (HESCs) into decidual cells, a process that critically controls embryo implantation. We now show an important role for androgen receptor (AR) signaling in this differentiation process. Decreased posttranslational modification of the AR by small ubiquitin-like modifier (SUMO)-1 in decidualizing cells accounted for increased responsiveness to androgen. By combining small interfering RNA technology with genome-wide expression profiling, we found that AR and progesterone receptor (PR) regulate the expression of distinct decidual gene networks. Ingenuity pathway analysis implicated a preponderance of AR-induced genes in cytoskeletal organization and cell motility, whereas analysis of AR-repressed genes suggested involvement in cell cycle regulation. Functionally, AR depletion prevented differentiation-dependent stress fiber formation and promoted motility and proliferation of decidualizing cells. In comparison, PR depletion perturbed the expression of many more genes, underscoring the importance of this nuclear receptor in diverse cellular functions. However, several PR-dependent genes encode for signaling intermediates, and knockdown of PR, but not AR, compromised activation of WNT/beta-catenin, TGFbeta/SMAD, and signal transducer and activator of transcription (STAT) pathways in decidualizing cells. Thus, the nonredundant function of the AR in decidualizing HESCs, centered on cytoskeletal organization and cell cycle regulation, implies an important role for androgens in modulating fetal-maternal interactions. Moreover, we show that PR regulates HESC differentiation, at least in part, by reprogramming growth factor and cytokine signal transduction.
Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Campus, London W12 0NN, United Kingdom.
Brianna
B
Cloke
Kaisa
K
Huhtinen
Luca
L
Fusi
Takeshi
T
Kajihara
Maria
M
Yliheikkilä
Ka-Kei
KK
Ho
Gijs
G
Teklenburg
Stuart
S
Lavery
Marius C
MC
Jones
Geoffrey
G
Trew
J Julie
JJ
Kim
Eric W-F
EW
Lam
Judith E
JE
Cartwright
Matti
M
Poutanen
Jan J
JJ
Brosens
D002478:Cells, Cultured; D003656:Decidua / Q000378:metabolism / Q000502:physiology*; D004717:Endometrium / Q000378:metabolism / Q000502:physiology*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D011499:Protein Processing, Post-Translational; D011944:Receptors, Androgen / Q000378:metabolism / Q000502:physiology*; D011980:Receptors, Progesterone / Q000502:physiology*; D025842:SUMO-1 Protein / Q000378:metabolism
C410798:AR protein, human; D011944:Receptors, Androgen; D011980:Receptors, Progesterone; D025842:SUMO-1 Protein