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Zhang D.,Zhejiang University | Zhang D.,Key Laboratory of Reproductive Genetics | Tan Y.-J.,Key Laboratory of Reproductive Genetics | Tan Y.-J.,Zhejiang University | And 6 more authors.
Molecular Aspects of Medicine | Year: 2012

Twelve water channels (aquaporins) are expressed in mammalian reproductive systems, and play very important roles in maintaining water homeostasis in reproductive cells. Impairment of their functions can result in attenuated male and female fertility. Alteration of AQPs expression is also found in reproductive tissues of the patients with polycystic ovarian syndrome, endometriosis or endometrium carcinoma. A lot of data have increased understanding of the functions and mechanisms of regulation of aquaporins at both the molecular and the clinical level. Researches have also focused on aquaporins as therapeutic targets. This review discusses recent advances in uncovering the physiological and pathophysiological roles of aquaporins in the reproductive systems. © 2012 Elsevier Ltd. All rights reserved.


Wang C.,Key Laboratory of Reproductive Genetics | Wang C.,Zhejiang University | Zhao L.,Key Laboratory of Reproductive Genetics | Zhao L.,Zhejiang University | And 2 more authors.
International Journal of Biological Sciences | Year: 2015

Telomere dysfunction is closely associated with human diseases such as cancer and ageing. Inappropriate changes in telomere length and/or structure result in telomere dysfunction. Telomeres have been considered to be transcriptionally silent, but it was recently demonstrated that mammalian telomeres are transcribed into telomeric repeat-containing RNA (TERRA). TERRA, a long non-coding RNA, participates in the regulation of telomere length, telomerase activity and heterochromatinization. The correct regulation of telomere length may be crucial to telomeric homeostasis and functions. Here, we summarize recent advances in our understanding of the crucial role of TERRA in the maintenance of telomere length, with focus on the variety of mechanisms by which TERRA is involved in the regulation of telomere length. This review aims to enable further understanding of how TERRA-targeted drugs can target telomere-related diseases. © 2015 Ivyspring International Publisher.


Qu F.,Zhejiang University | Qu F.,Key Laboratory of Reproductive Genetics | Wang F.-F.,Zhejiang University | Yin R.,Zhejiang University | And 16 more authors.
Journal of Molecular Medicine | Year: 2012

The objective of this study was to explore whether hyperandrogenism induces epigenetic alterations of peroxisome proliferator-activated receptor gamma 1 (PPARG1), nuclear corepressor 1 (NCOR1), and histone deacetylase 3 (HDAC3) genes in granulosa cells (GCs) of polycystic ovary syndrome (PCOS) women and whether these alterations are involved in the ovarian dysfunction induced by hyperandrogenism. Thirty-two infertile PCOS women and 147 infertile women with tubal blockage were recruited. PCOS women were divided into the hyperandrogenism (HA) PCOS group (n013) and nonhyperandrogenism (N-HA) PCOS group (n019). Sixty female Sprague-Dawley rats were used for PCOS model establishment. In GCs of HA PCOS women, PPARG1 mRNA expression was lower, whereas NCOR1 and HDAC3 mRNA expression were higher than N-HA PCOS women and controls (P<0.05). When all women were divided into successful and failed pregnancy subgroups according to the following clinical pregnancy outcome, we found lower PPARG1 mRNA levels and higher NCOR1 and HDAC3 mRNA levels in the failed subgroup of HA PCOS (P<0.05). Two hypermethylated CpG sites in the PPARG1 promoter and five hypomethylated CpG sites in the NCOR1 promoter were observed only in HA PCOS women (P<0.01 to P < 0.0005). The acetylation levels of histone H3 at lysine 9 and p21 mRNA expression were decreased in human GCs treated with dihydrotestosterone in vitro (P<0.05). PCOS rat models also showed alterations of PPARG1, NCOR1, and HDAC3 mRNA expression and methylation changes of PPARG1 and NCOR1, consistent with the results from humans. Hyperandrogenism induces the epigenetic alterations of PPARG1, NCOR1, and HDAC3 in GCs, which are involved in the ovarian dysfunction of HA PCOS. © Springer-Verlag 2012.


Yin L.-J.,Zhejiang University | Zhang Y.,Zhejiang University | Zhang Y.,Key Laboratory of Reproductive Genetics | Lv P.-P.,Key Laboratory of Reproductive Genetics | And 10 more authors.
BMC Medicine | Year: 2012

Background: Early pregnancy loss (EPL) is a frustrating clinical problem, whose mechanisms are not completely understood. DNA methylation, which includes maintenance methylation and de novo methylation directed by DNA methyltransferases (DNMTs), is important for embryo development. Abnormal function of these DNMTs may have serious consequences for embryonic development.Methods: To evaluate the possible involvement of DNA methylation in human EPL, the expression of DNMT proteins and global methylation of DNA were assessed in villous or decidua from EPL patients. The association of maintenance methylation with embryo implantation and development was also examined.Results: We found that DNMT1 and DNMT3A were both expressed in normal human villous and decidua. DNMT1 expression and DNA global methylation levels were significantly down-regulated in villous of EPL. DNMT3A expression was not significantly changed in the EPL group compared to controls in either villous or decidua. We also found that disturbance of maintenance methylation with a DNMT1 inhibitor may result in a decreased global DNA methylation level and impaired embryonic development in the mouse model, and inhibit in vitro embryo attachment to endometrial cells.Conclusions: Our results demonstrate that defects in DNA maintenance methylation in the embryo, not in the mother, are associated with abnormal embryonic implantation and development. The findings of the current study provide new insights into the etiology of EPL. © 2012 Yin et al; licensee BioMed Central Ltd.


Lu Y.-C.,Zhejiang University | Ding G.-L.,Zhejiang University | Yang J.,Zhejiang University | Zhang Y.-L.,Zhejiang University | And 9 more authors.
Human Reproduction | Year: 2012

Background The present study was designed to investigate the expression of small-conductance calcium-activated K+ channels 3 (SK3) in preimplantation embryos and to explore their role in the underlying mechanism of blastocyst hatching. Methods Human preimplantation embryos were donated by patients who achieved successful pregnancy with in vitro fertilization. Mouse preimplantation embryos in different stages were collected and cultured with or without siRNA cell injection. The expression of SK3 was examined by RTPCR, quantitative real-time PCR, western blot and immunofluorescence. Functional expression of SK3 was investigated using the patch-clamp technique. [Ca 2]i was measured by fluorescent imaging. Embryos were cultured in vitro to investigate the effect of SK3 knockdown or apamin, an SK3 inhibitor, on blastocyst hatching and F-actin formation. Results In human blastocysts, the level of SK3 expression was significantly lower in blastocysts that failed to hatch than in blastocysts that hatched successfully. In mouse embryos, SK3 mRNA and protein were not found in zygotes, but were detected from the 2-cell stage onward, with the highest levels observed in blastocysts. SK3 was predominately located in the trophectoderm cell membrane of expanded blastocysts. SK3 knockdown in trophectoderm cells not only suppressed the SK3 current, but also reduced [Ca2]i elevation and membrane potential hyperpolarization induced by thapsigargin. Although the formation of expanded blastocysts was not affected, blastocyst hatching and F-actin formation were significantly inhibited after SK3 knockdown in trophectoderm cells. Conclusions SK3-mediated [Ca 2]i elevation and membrane potential hyperpolarization in trophectoderm cells are important for blastocyst hatching, and defects in SK3 expression may contribute to infertility. © 2012 The Autho.


Zou L.-B.,Zhejiang University | Zhang R.-J.,Zhejiang University | Tan Y.-J.,Zhejiang University | Ding G.-L.,Zhejiang University | And 14 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2011

Background: Accumulating evidence suggests that aquaporins (AQP) can facilitate cell migration, invasion, and proliferation in tumor development in addition to water transport. Objective: The aim of this study was to examine AQP2 expression in the endometrial tissues from patients with endometrial carcinoma (EC) and determine the roles and mechanisms of AQP2 in estrogen-related cell migration, invasion, adhesion, and proliferation of Ishikawa (IK) cells. Approach: AQP2 expression levels were measured in human endometrial cells and estradiol (E 2)- treated IK cells, and the estrogen-response element was identified. After blocking down and up-regulating the endogenous expression of AQP2 in IK cells, cell morphology, capacity for invasion, migration and adhesion, and expression markers of membrane/ cytoskeleton were analyzed. Results: AQP2 was expressed in endometrial tissues from patients with EC and endometriosis, both of which are estrogen-dependent diseases. In IK cells, E 2 dose-dependently increased AQP2 expression, which was blocked by the estrogen receptor inhibitor ICI182780. An estrogen-response element was identified in the AQP2 promoter. E 2 significantly increased the migration, invasion, adhesion, and proliferation of IK cells. AQP2 knockdown attenuated E 2-enhanced migration, invasion, and adhesion. AQP2 knockdown reduced not only the E 2-enhanced expression of F-actin and annexin-2 but also the E 2-induced alteration of cell morphology. Moreover, higher expression levels of F-actin and annexin-2 were detected in the endometrial tissues from patients with EC. Conclusions: AQP2 mediates E 2-enhanced migration, invasion, and adhesion through alteration of F-actin and annexin-2 expression and reorganization of F-actin, and inhibition of AQP may be a potential method for antitumor therapy. Copyright © 2011 by The Endocrine Society.


Ding G.-L.,Zhejiang University | Wang F.-F.,Zhejiang University | Shu J.,Zhejiang University | Tian S.,Zhejiang University | And 10 more authors.
Diabetes | Year: 2012

Gestational diabetes mellitus (GDM) has been shown to be associated with high risk of diabetes in offspring. However, the mechanisms involved and the possibilities of transgenerational transmission are still unclear. We intercrossed male and female adult control and first-generation offspring of GDM (F1-GDM) mice to obtain the second-generation (F2) offspring in four groups: C♂-C♀, C♂-GDM♀, GDM♂-C♀, and GDM♂-GDM♀. We found that birth weight significantly increased in F2 offspring through the paternal line with impaired glucose tolerance (IGT). Regardless of birth from F1-GDM with or without IGT, high risk of IGT appeared as early as 3 weeks in F2 offspring and progressed through both parental lineages, especial the paternal line. IGT in male offspring was more obvious than that in females, with parental characteristics and sex-specific transmission. In both F1 and F2 offspring of GDM, the expression of imprinted genes Igf2 and H19 was downregulated in pancreatic islets, caused by abnormal methylation status of the differentially methylated region, which may be one of the mechanisms for impaired islet ultrastructure and function. Furthermore, altered Igf2 and H19 gene expression was found in sperm of adult F1-GDM, regardless of the presence of IGT, indicating that changes of epigenetics in germ cells contributed to transgenerational transmission. © 2012 by the American Diabetes Association.


Guo J.,Zhejiang University | Tian T.,Zhejiang University | Lu D.,Zhejiang University | Xia G.,Zhejiang University of Science and Technology | And 4 more authors.
Journal of Obstetrics and Gynaecology Research | Year: 2012

Aim: To clarify the alterations of myostatin, a member of the transforming growth factor-b superfamily, and follistatin-like 3 (FSTL3), a binding protein for myostatin, in pre-eclamptic women. Methods: Samples of blood and placenta were collected from 40 pre-eclamptic women and 40 controls. The serum level and placental expression of FSTL3 and myostatin were determined with enzyme-linked immunosorbent assay, real-time polymerized chain reaction and western blotting. Results: The serum levels of myostatin and FSTL3 were significantly higher in pre-eclamptic women than in the controls (P < 0.001 for both). Placental expression of myostatin and FSTL3 were also significantly increased in the pre-eclamptic placenta compared with that of the controls (P < 0.001 for both); however, there were no significant differences in myostatin or FSTL3 in either the maternal serum or the placenta in women with mild or severe pre-eclampsia (P > 0.05 for both). Conclusion: The serum levels and placental expression of myostatin and FSTL3 are elevated in pre-eclampsia, suggesting the role of myostatin and its binding protein in pre-eclampsia. © 2012 The Authors.


Liu X.-M.,Zhejiang University | Ding G.-L.,Zhejiang University | Jiang Y.,Zhejiang University | Pan H.-J.,Zhejiang University | And 7 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Background: Low expression levels of S100A11 proteins were demonstrated in the placental villous tissue of patients with early pregnancy loss, and S100A11 is a Ca2+-binding protein that interprets the calcium fluctuations and elicits various cellular responses. Objectives: The objective of the study was to determine S100A11 expression in human endometrium and its roles in endometrial receptivity and embryo implantation. Methods: S100A11 expression in human endometrium was analyzed using quantitative RT-PCR, Western blot, and immunohistochemical techniques. The effects of S100A11 on embryo implantation were examined using in vivo mouse model, and JAr (a human choriocarcinoma cell line) spheroid attachment assays. The effects of endometrial S100A11 on factors related to endometrial receptivity and immune responses were examined. Using a fluorescence method, we examined the changes in cytosolic Ca2+ and Ca2+ release from intracellular stores in epidermal growth factor (EGF)-treated endometrial cells transfected with or without S100A11 small interfering RNA. Results: S100A11 was expressed in human endometrium. S100A11 protein levels were significantly lower in endometrium of women with failed pregnancy than that in women with successful pregnancy outcomes. The knockdown of endometrial S100A11 not only reduced embryo implantation rate in mouse but also had adverse effects on the expression of factors related to endometrial receptivity and immune responses in human endometrial cells. Immunofluorescence analysis showed that S100A11 proteins were mainly localized in endoplasmic reticulum. The EGF up-regulated endometrial S100A11 expression and promoted the Ca2+ uptake and release from Ca2+ stores, which was inhibited by the knockdown of S100A11. Conclusions: Endometrial S100A11 is a crucial intermediator in EGF-stimulated embryo adhesion, endometrium receptivity, and immunotolerance via affecting Ca2+ uptake and release from intracellular Ca2+ stores. Down-regulation of S100A11 may cause reproductive failure. Copyright © 2012 by The Endocrine Society.


Lou H.,Zhejiang University | Lou H.,Key Laboratory of Reproductive Genetics | Le F.,Zhejiang University | Zheng Y.,Zhejiang University | And 9 more authors.
Fertility and Sterility | Year: 2014

Objective To evaluate the cholesterol metabolism linked to assisted reproductive technology (ART) by analyzing the expression levels and DNA methylation patterns of the insulin-induced gene (INSIG), sterol regulatory element-binding protein (SREBP), and SREBP cleavage-activating protein in the fetus and placenta. Design Experimental research study. Setting An IVF center, university-affiliated teaching hospital. Patient(s) Four patients groups were recruited: pregnancies after IVF/intracytoplasmic sperm injection (ICSI) (n = 55), natural pregnancies (n = 40), multifetal reduction after IVF/ICSI (n = 56), and multifetal reduction after controlled ovarian hyperstimulation (COH) (n = 42). Intervention(s) Expression and DNA methylation of INSIG-SREBP- SREBP cleavage-activating protein in the fetus and placenta samples were determined. Main Outcome Measure(s) The expression and DNA methylation patterns were tested by real-time quantitative polymerase chain reaction (PCR) and pyrosequencing. Result(s) In the ICSI treatment group, significantly higher levels of triglycerides and apolipoprotein-B were observed in cord blood compared with controls. Meanwhile, in ICSI-conceived fetuses, the expression of INSIG1 was significantly higher, and methylation rates were lower, than in the IVF and control groups. Furthermore, in the placenta, the INSIG1 and SREBF1 transcripts were also significantly higher with lower methylation rates in the ICSI group than in the IVF and control groups. Conclusion(s) Our results indicated that the dysregulation of INSIG1 and SREBF1 caused by ART were observed not only in the fetus but also in the placenta, primarily in the ICSI group. However, the long-term sequelae of this dysregulation should be closely followed. © 2014 American Society for Reproductive Medicine, Published by Elsevier Inc. All rights reserved.

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