title: The clock protein period 2 synchronizes mitotic expansion and decidual transformation of human endometrial stromal cells.
abstract: Implantation requires coordinated interactions between the conceptus and surrounding decidual cells, but the involvement of clock genes in this process is incompletely understood. Circadian oscillations are predicated on transcriptional-translational feedback loops, which balance the activities of the transcriptional activators CLOCK (circadian locomotor output cycles kaput) and brain muscle arnt-like 1 and repressors encoded by PER (Period) and Cryptochrome genes. We show that loss of PER2 expression silences circadian oscillations in decidualizing human endometrial stromal cells (HESCs). Down-regulation occurred between 12 and 24 hours following differentiation and coincided with reduced CLOCK binding to a noncanonical E-box enhancer in the PER2 promoter. RNA sequencing revealed that premature inhibition of PER2 by small interfering RNA knockdown leads to a grossly disorganized decidual response. Gene ontology analysis highlighted a preponderance of cell cycle regulators among the 1121 genes perturbed upon PER2 knockdown. Congruently, PER2 inhibition abrogated mitotic expansion of differentiating HESCs by inducing cell cycle block at G2/M. Analysis of 70 midluteal endometrial biopsies revealed an inverse correlation between PER2 transcript levels and the number of miscarriages in women suffering reproductive failure (Spearman rank test, ρ = -0.3260; P = 0.0046). Thus, PER2 synchronizes endometrial proliferation with initiation of aperiodic decidual gene expression; uncoupling of these events may cause recurrent pregnancy loss.
authors.affiliation: *Division of Translational & Systems Medicine, Warwick Medical School, and Warwick Systems Biology Centre, University of Warwick, Coventry, United Kingdom; and Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine, London, United Kingdom.
authors.forename: Joanne
authors.initials: J
authors.lastname: Muter
authors.affiliation: *Division of Translational & Systems Medicine, Warwick Medical School, and Warwick Systems Biology Centre, University of Warwick, Coventry, United Kingdom; and Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine, London, United Kingdom.
authors.forename: Emma S
authors.initials: ES
authors.lastname: Lucas
authors.affiliation: *Division of Translational & Systems Medicine, Warwick Medical School, and Warwick Systems Biology Centre, University of Warwick, Coventry, United Kingdom; and Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine, London, United Kingdom.
authors.forename: Yi-Wah
authors.initials: YW
authors.lastname: Chan
authors.affiliation: *Division of Translational & Systems Medicine, Warwick Medical School, and Warwick Systems Biology Centre, University of Warwick, Coventry, United Kingdom; and Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine, London, United Kingdom.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Brighton
authors.affiliation: *Division of Translational & Systems Medicine, Warwick Medical School, and Warwick Systems Biology Centre, University of Warwick, Coventry, United Kingdom; and Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine, London, United Kingdom.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Moore
authors.affiliation: *Division of Translational & Systems Medicine, Warwick Medical School, and Warwick Systems Biology Centre, University of Warwick, Coventry, United Kingdom; and Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine, London, United Kingdom.
authors.forename: Lauren
authors.initials: L
authors.lastname: Lacey
authors.affiliation: *Division of Translational & Systems Medicine, Warwick Medical School, and Warwick Systems Biology Centre, University of Warwick, Coventry, United Kingdom; and Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine, London, United Kingdom.
authors.forename: Siobhan
authors.initials: S
authors.lastname: Quenby
authors.affiliation: *Division of Translational & Systems Medicine, Warwick Medical School, and Warwick Systems Biology Centre, University of Warwick, Coventry, United Kingdom; and Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine, London, United Kingdom.
authors.forename: Eric W-F
authors.initials: EW
authors.lastname: Lam
authors.affiliation: *Division of Translational & Systems Medicine, Warwick Medical School, and Warwick Systems Biology Centre, University of Warwick, Coventry, United Kingdom; and Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine, London, United Kingdom j.j.brosens@warwick.ac.uk.
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Brosens
mesh_terms: D000026:Abortion, Habitual / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002940:Circadian Rhythm; D010064:Embryo Implantation / Q000235:genetics* / Q000502:physiology*; D004717:Endometrium / Q000166:cytology / Q000502:physiology; D004742:Enhancer Elements, Genetic; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints; D055785:Gene Knockdown Techniques; D006801:Humans; D008938:Mitosis / Q000235:genetics / Q000502:physiology; D056950:Period Circadian Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology*; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D017154:Stromal Cells / Q000166:cytology / Q000502:physiology
chemical_list: C421902:PER2 protein, human; D056950:Period Circadian Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering
keywords: cell cycle; circadian rhythm; endometrium; miscarriage