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 ISSN 0892-6638.

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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 Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Cell & Developmental Biology Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Reproductive Health ( - until July 2016) Faculty of Science, Engineering and Medicine > Research Centres > Warwick Systems Biology Centre Faculty of Science, Engineering and Medicine > 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:	Date Event 29 April 2015 Published 8 January 2015 Available
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 (Creative Commons)
Date of first compliant deposit:	29 December 2015
Date of first compliant Open Access:	29 December 2015
Funder:	University Hospitals Coventry and Warwickshire NHS Trust, Warwick Medical School, University of Warwick Vice Chancellor Scholarship
Open Access Version:	Publisher

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