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The clock protein period 2 synchronizes mitotic expansion and decidual transformation of human endometrial stromal cells

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Muter, Joanne, Lucas, Emma S., Chan, Yi-Wah, Brighton, Paul (Paul J.), Moore, Jonathan D., Lacey, Lauren, Quenby, Siobhan, Lam, Eric W.-F. and Brosens, Jan J. (2015) The clock protein period 2 synchronizes mitotic expansion and decidual transformation of human endometrial stromal cells. The FASEB Journal, Volume 29 (Number 4). pp. 1603-1614. doi:10.1096/fj.14-267195

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Official URL: http://dx.doi.org/10.1096/fj.14-267195

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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.-Muter, J., Lucas, E. S., Chan, Y.-W., Brighton, P. J., Moore, J. D., Lacey, L., Quenby, S., Lam, E. W.-F., Brosens, J. J. The clock protein period 2 synchronizes mitotic expansion and decidual transformation of human endometrial stromal cells.

Item Type: Journal Article
Subjects: R Medicine > RG Gynecology and obstetrics
Divisions: Faculty of Medicine > Warwick Medical School > Biomedical Sciences > Cell & Developmental Biology
Faculty of Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Reproductive Health ( - until July 2016)
Faculty of Science > Centre for Systems Biology
Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH): Circadian rhythms, Endometrium, Miscarriage
Journal or Publication Title: The FASEB Journal
Publisher: Federation of American Societies for Experimental Biology
ISSN: 0892-6638
Official Date: 29 April 2015
Dates:
DateEvent
29 April 2015Published
8 January 2015Available
Volume: Volume 29
Number: Number 4
Number of Pages: 12
Page Range: pp. 1603-1614
DOI: 10.1096/fj.14-267195
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access
Funder: University Hospitals Coventry and Warwickshire NHS Trust, Warwick Medical School, University of Warwick Vice Chancellor Scholarship
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