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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
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 | ||||||
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| 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 |
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| 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: |
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| Date of first compliant deposit: | 29 December 2015 | ||||||
| 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 | ||||||
| Open Access Version: |
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