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The clock protein period 2 synchronizes mitotic expansion and decidual transformation of human endometrial stromal cells
Author(s) -
Muter Joanne,
Lucas Emma S.,
Chan YiWah,
Brighton Paul J.,
Moore Jonathan D.,
Lacey Lauren,
Quenby Siobhan,
Lam Eric W.F.,
Brosens Jan J.
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.14-267195
Subject(s) - per2 , biology , gene knockdown , microbiology and biotechnology , clock , circadian clock , circadian rhythm , period (music) , gene , endocrinology , genetics , physics , acoustics
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. FASEB J. 29, 1603‐1614 (2015). www.fasebj.org