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      Impaired decidualization caused by downregulation of circadian clock gene BMAL1 contributes to human recurrent miscarriage†

      1 , 2 , 3 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 4 , 2

      Biology of Reproduction

      Oxford University Press (OUP)

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          Abstract

          Recurrent miscarriage (RM) is characterized by two or more consecutive losses of a clinically established intrauterine pregnancy at early gestation. To date, the etiology of RM remains poorly understood. Impaired decidualization is thought to predispose women to subsequent pregnancy failure. The transcriptional factor brain and muscle aryl hydrocarbon receptor nuclear translocator-like (BMAL1) controls circadian rhythms and regulates a very large diversity of physiological processes. BMAL1 is essential for fertility. Here, we investigated the expression and function of BMAL1 in human decidualization and its relation with RM. A total of 39 decidua samples were collected. We also examined human endometrial stromal cells (HESCs) and primary endometrial stromal cells (ESCs), and primary decidual stromal cells (DSCs) isolated from decidua of first-trimester pregnancies. Compared to normal pregnant women, the expression of BMAL1 was reduced in the decidual tissues from individuals with RM. After in vitro induction of decidualization, the transcription of BMAL1 in both HESCs and primary ESCs was increased. This is in line with the relatively higher expression of BMAL1 in DSCs than in ESCs. Silencing of BMAL1 resulted in impaired decidualization. Moreover, levels of tissue inhibitors of metalloproteinases (TIMPs) increased significantly upon decidualization. Further experiments demonstrated that BMAL1 silencing curtails the ability of DSCs to restrict excessive trophoblast invasion via downregulation of TIMP3. Our study demonstrates a functional role for BMAL1 during decidualization: the downregulation of BMAL1 in RM leads to impaired decidualization and aberrant trophoblast invasion by regulating TIMP3 and consequently predisposing individuals for RM.

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          Most cited references 35

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          Recurrent miscarriage.

           Raj Rai,  Lesley Regan (2006)
          Many human conceptions are genetically abnormal and end in miscarriage, which is the commonest complication of pregnancy. Recurrent miscarriage, the loss of three or more consecutive pregnancies, affects 1% of couples trying to conceive. It is associated with psychological morbidity, and has often proven to be frustrating for both patient and clinician. A third of women attending specialist clinics are clinically depressed, and one in five have levels of anxiety that are similar to those in psychiatric outpatient populations. Many conventional beliefs about the cause and treatment of women with recurrent miscarriage have not withstood scrutiny, but progress has been made. Research has emphasised the importance of recurrent miscarriage in the range of reproductive failure linking subfertility and late pregnancy complications and has allowed us to reject practice based on anecdotal evidence in favour of evidence-based management.
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            Cyclic decidualization of the human endometrium in reproductive health and failure.

            Decidualization denotes the transformation of endometrial stromal fibroblasts into specialized secretory decidual cells that provide a nutritive and immunoprivileged matrix essential for embryo implantation and placental development. In contrast to most mammals, decidualization of the human endometrium does not require embryo implantation. Instead, this process is driven by the postovulatory rise in progesterone levels and increasing local cAMP production. In response to falling progesterone levels, spontaneous decidualization causes menstrual shedding and cyclic regeneration of the endometrium. A growing body of evidence indicates that the shift from embryonic to maternal control of the decidual process represents a pivotal evolutionary adaptation to the challenge posed by invasive and chromosomally diverse human embryos. This concept is predicated on the ability of decidualizing stromal cells to respond to individual embryos in a manner that either promotes implantation and further development or facilitates early rejection. Furthermore, menstruation and cyclic regeneration involves stem cell recruitment and renders the endometrium intrinsically capable of adapting its decidual response to maximize reproductive success. Here we review the endocrine, paracrine, and autocrine cues that tightly govern this differentiation process. In response to activation of various signaling pathways and genome-wide chromatin remodeling, evolutionarily conserved transcriptional factors gain access to the decidua-specific regulatory circuitry. Once initiated, the decidual process is poised to transit through distinct phenotypic phases that underpin endometrial receptivity, embryo selection, and, ultimately, resolution of pregnancy. We discuss how disorders that subvert the programming, initiation, or progression of decidualization compromise reproductive health and predispose for pregnancy failure.
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              Metabolism and cancer: the circadian clock connection.

              Circadian rhythms govern a remarkable variety of metabolic and physiological functions. Accumulating epidemiological and genetic evidence indicates that the disruption of circadian rhythms might be directly linked to cancer. Intriguingly, several molecular gears constituting the clock machinery have been found to establish functional interplays with regulators of the cell cycle, and alterations in clock function could lead to aberrant cellular proliferation. In addition, connections between the circadian clock and cellular metabolism have been identified that are regulated by chromatin remodelling. This suggests that abnormal metabolism in cancer could also be a consequence of a disrupted circadian clock. Therefore, a comprehensive understanding of the molecular links that connect the circadian clock to the cell cycle and metabolism could provide therapeutic benefit against certain human neoplasias.
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                Author and article information

                Journal
                Biology of Reproduction
                Oxford University Press (OUP)
                0006-3363
                1529-7268
                July 2019
                July 01 2019
                April 15 2019
                July 2019
                July 01 2019
                April 15 2019
                : 101
                : 1
                : 138-147
                Affiliations
                [1 ]Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
                [2 ]Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China
                [3 ]bstetrical Department, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
                [4 ]Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Ji’nan, Shandong, China
                Article
                10.1093/biolre/ioz063
                © 2019

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