Papers by Caterina Clementi
Journal of Assisted Reproduction and Genetics
Endometriosis affects ∼10% of women of reproductive age. It is characterized by the growth of end... more Endometriosis affects ∼10% of women of reproductive age. It is characterized by the growth of endometrial-like tissue outside the uterus and is frequently associated with severe pain and infertility. We performed the largest endometriosis genome-wide association study (GWAS) to date, with 37,183 cases and 251,258 controls. All women were of European ancestry. We also performed the first GWAS of endometriosis-related infertility, including 2,969 cases and 3,770 controls. Our endometriosis GWAS study replicated, at genome-wide significance, seven loci identified in previous endometriosis GWASs (CELA3A-CDC42, SYNE1, KDR, FSHB-ARL14EP, GREB1, ID4, and CEP112) and identified seven new candidate loci with genome-wide significance (NGF, ATP1B1-F5, CD109, HEY2, OSR2-VPS13B, WT1, and TEX11-SLC7A3). No loci demonstrated genome-wide significance for endometriosis-related infertility, however, the three most strongly associated loci (MCTP1, EPS8L3-CSF1, and LPIN1) were in or near genes associat...
The Journal of clinical investigation, Jan 2, 2018
Uncovering the causes of pregnancy complications such as preterm labor requires greater insight i... more Uncovering the causes of pregnancy complications such as preterm labor requires greater insight into how the uterus remains in a noncontractile state until term and then surmounts this state to enter labor. Here, we show that dynamic generation and erasure of the repressive histone modification tri-methyl histone H3 lysine 27 (H3K27me3) in decidual stromal cells dictate both elements of pregnancy success in mice. In early gestation, H3K27me3-induced transcriptional silencing of select gene targets ensured uterine quiescence by preventing the decidua from expressing parturition-inducing hormone receptors, manifesting type 1 immunity, and most unexpectedly, generating myofibroblasts and associated wound-healing responses. In late gestation, genome-wide H3K27 demethylation allowed for target gene upregulation, decidual activation, and labor entry. Pharmacological inhibition of H3K27 demethylation in late gestation not only prevented term parturition, but also inhibited delivery while m...
Fertility and Sterility
tion). These 23,300 articles were then manually screened to remove false positives and identify f... more tion). These 23,300 articles were then manually screened to remove false positives and identify false negatives, yielding 4,758 articles studying 1713 unique genetic regions. We applied ACMG/AMP guidelines to rank these genes according to the level of evidence supporting their association with the diagnosis of interest: 'definitive', 'strong', 'moderate', 'limited', or 'no evidence'. No genetic associations met the criteria for definitive evidence, therefore, articles relating to genes that fit the criteria for strong evidence were analyzed further in a series of random effects model meta-analyses to assess which reported associations held up on an individual variant level. Per PRISMA guidelines, two independent reviewers recorded R137 data points per case-control study and met to resolve conflicts. Variants were excluded from analysis if there were <2 published studies, overlapping cohorts, or the risk allele could not be determined. Significance was defined by setting a false discovery rate threshold of 5%. RESULT(S): In total, 1,071,165 unique data points related to 2248 variants within 201 genetic regions meeting the criteria for ''strong evidence'' were captured upstream of meta-analyses. 427 variants met inclusion criteria for meta-analysis, and 71 of these demonstrated a statistically significant association. Notably, three gene variants were found to have Odds Ratio (OR) R3.5 and allele frequencies (AF) < 0.01, suggesting these variants are rare and exert a strong-effect. The genes containing these 71 variants were found to function in just 8 biological processes related to reproduction: blood circulation, cell proliferation/differentiation, DNA replication and repair, glucose homeostasis, hormone regulation, immune response regulation, ovarian follicle development, and tissue remodeling. CONCLUSION(S): Our work identifies and characterizes 71 genetic markers significantly associated with reproductive conditions, including three with OR R3.5. None are currently used in routine practice. The identification of these markers and associated ORs for reproductive conditions, offers the potential for new applications of personalized reproductive medicine. FINANCIAL SUPPORT: Celmatix Inc. References: None.
Endocrinology, Apr 1, 2017
In women, the window of implantation is limited to a brief 2- to 3-day period characterized by op... more In women, the window of implantation is limited to a brief 2- to 3-day period characterized by optimal levels of circulating ovarian hormones and a receptive endometrium. Although the window of implantation is assumed to occur 8 to 10 days after ovulation in women, molecular markers of endometrial receptivity are necessary to determine optimal timing prior to embryo transfer. Previous studies showed that members of the bone morphogenetic protein (BMP) family are expressed in the uterus necessary for female fertility; however, the role of BMP7 during implantation and in late gestation is not known. To determine the contribution of BMP7 to female fertility, we generated Bmp7flox/flox-Pgr-cre+/- [BMP7 conditional knockout (cKO)] mice. We found that absence of BMP7 in the female reproductive tract resulted in subfertility due to uterine defects. At the time of implantation, BMP7 cKO females displayed a nonreceptive endometrium with elevated estrogen-dependent signaling. These implantati...
Biology of Reproduction, 2010
Biology of reproduction, Aug 1, 2016
Pregnancy is a complex physiological process tightly controlled by the interplay among hormones, ... more Pregnancy is a complex physiological process tightly controlled by the interplay among hormones, morphogens, transcription factors, and signaling pathways. Although recent studies using genetically engineered mouse models have revealed that ligands and receptors of transforming growth factor beta (TGFbeta) and bone morphogenetic protein (BMP) signaling pathways are essential for multiple reproductive events during pregnancy, the functional role of SMAD transcription factors, which serve as the canonical signaling platform for the TGFbeta/BMP pathways, in the oviduct and uterus is undefined. Here, we used a mouse model containing triple conditional deletion of the BMP receptor signaling Smads (Smad1 and Smad5) and Smad4, the central mediator of both TGFbeta and BMP signaling, to investigate the role of the SMADs in reproductive tract structure and function in cells from the Amhr2 lineage. Unlike the respective single- or double-knockouts, female Smad1(flox/flox) Smad5(flox/flox) Smad...
The Endocrine Society's 93rd Annual Meeting & Expo, June 4–7, 2011 - Boston, 2011
Proceedings of the National Academy of Sciences of the United States of America, Jan 19, 2016
The window of implantation is defined by the inhibition of uterine epithelial proliferation, stru... more The window of implantation is defined by the inhibition of uterine epithelial proliferation, structural epithelial cell remodeling, and attenuated estrogen (E2) response. These changes occur via paracrine signaling between the uterine epithelium and stroma. Because implantation defects are a major cause of infertility in women, identifying these signaling pathways will improve infertility interventions. Bone morphogenetic proteins (BMPs) are TGF-β family members that regulate the postimplantation and midgestation stages of pregnancy. In this study, we discovered that signaling via activin-like kinase 3 (ALK3/BMPR1A), a BMP type 1 receptor, is necessary for blastocyst attachment. Conditional knockout (cKO) of ALK3 in the uterus was obtained by producing Alk3(flox) (/flox)-Pgr-cre-positive females. Alk3 cKO mice are sterile and have defects in the luminal uterine epithelium, including increased microvilli density and maintenance of apical cell polarity. Moreover, Alk3 cKO mice exhibit...
Molecular endocrinology (Baltimore, Md.), Jan 20, 2015
The placenta is the first organ to develop after fertilization. It forms an interface between the... more The placenta is the first organ to develop after fertilization. It forms an interface between the maternal uterus and growing fetus to allow nutrient uptake, waste elimination, and gas exchange for a successful pregnancy in both mice and humans. In the past two decades, in vivo and in vitro approaches have been used to show that several members of the transforming growth factor β (TGF-β) superfamily regulate embryo implantation and placental development. Nodal, a TGF-β superfamily ligand, is essential for mesendoderm formation and left-right axis patterning during embryogenesis and Nodal null mutants exhibit abnormal placental organization with expansion of trophoblast giant cells and a decrease of spongiotrophoblast and labyrinth. To better understand the importance of Nodal signaling in the uterus, we established a mouse model to conditionally ablate ALK4 (the Nodal type 1 receptor) using Cre recombinase driven by the progesterone receptor (Pgr-Cre) promoter sequences. Alk4 cKO fe...
Yen & Jaffe's Reproductive Endocrinology, 2014
PLoS Genetics, 2013
Implantation of a blastocyst in the uterus is a multistep process tightly controlled by an intric... more Implantation of a blastocyst in the uterus is a multistep process tightly controlled by an intricate regulatory network of interconnected ovarian, uterine, and embryonic factors. Bone morphogenetic protein (BMP) ligands and receptors are expressed in the uterus of pregnant mice, and BMP2 has been shown to be a key regulator of implantation. In this study, we investigated the roles of the BMP type 1 receptor, activin-like kinase 2 (ALK2), during mouse pregnancy by producing mice carrying a conditional ablation of Alk2 in the uterus (Alk2 cKO mice). In the absence of ALK2, embryos demonstrate delayed invasion into the uterine epithelium and stroma, and upon implantation, stromal cells fail to undergo uterine decidualization, resulting in sterility. Mechanistically, microarray analysis revealed that CCAAT/enhancer-binding protein b (Cebpb) expression is suppressed during decidualization in Alk2 cKO females. These findings and the similar phenotypes of Cebpb cKO and Alk2 cKO mice lead to the hypothesis that BMPs act upstream of CEBPB in the stroma to regulate decidualization. To test this hypothesis, we knocked down ALK2 in human uterine stromal cells (hESC) and discovered that ablation of ALK2 alters hESC decidualization and suppresses CEBPB mRNA and protein levels. Chromatin immunoprecipitation (ChIP) analysis of decidualizing hESC confirmed that BMP signaling proteins, SMAD1/5, directly regulate expression of CEBPB by binding a distinct regulatory sequence in the 39 UTR of this gene; CEBPB, in turn, regulates the expression of progesterone receptor (PGR). Our work clarifies the conserved mechanisms through which BMPs regulate peri-implantation in rodents and primates and, for the first time, uncovers a linear pathway of BMP signaling through ALK2 to regulate CEBPB and, subsequently, PGR during decidualization.
Journal of Clinical Investigation, 2013
Abnormalities in cell-cell communication and growth factor signaling pathways can lead to defects... more Abnormalities in cell-cell communication and growth factor signaling pathways can lead to defects in maternal-fetal interactions during pregnancy, including immunologic rejection of the fetal/placental unit. In this study, we discovered that bone morphogenetic protein receptor type 2 (BMPR2) is essential for postimplantation physiology and fertility. Despite normal implantation and early placental/fetal development, deletion of Bmpr2 in the uterine deciduae of mice triggered midgestation abnormalities in decidualization that resulted in abnormal vascular development, trophoblast defects, and a deficiency of uterine natural killer cells. Absence of BMPR2 signaling in the uterine decidua consequently suppressed IL-15, VEGF, angiopoietin, and corin signaling. Disruption of these pathways collectively lead to placental abruption, fetal demise, and female sterility, thereby placing BMPR2 at a central point in the regulation of several physiologic signaling pathways and events at the maternal-fetal interface. Since trophoblast invasion and uterine vascular modification are implicated in normal placentation and fetal growth in humans, our findings suggest that abnormalities in uterine BMPR2mediated signaling pathways can have catastrophic consequences in women for the maintenance of pregnancy. Conflict of interest: The authors have declared that no conflict of interest exists.
Endocrine Reviews, 2010
Vitamin D receptor (VDR) is activated by natural ligands, 1␣, 25-dihydroxy-vitamin D 3 (1␣, 25(OH... more Vitamin D receptor (VDR) is activated by natural ligands, 1␣, 25-dihydroxy-vitamin D 3 (1␣, 25(OH) 2-D 3) and lithocholic acid (LCA). Our previous study shows that VDR is expressed in human hepatocytes, and VDR ligands inhibit bile acid synthesis and transcription of the gene encoding cholesterol 7␣-hydroxylase (CYP7A1). Primary human hepatocytes were used to study LCA and 1␣, 25(OH) 2-D 3 activation of VDR signaling. Confocal immunofluorescent microscopy imaging and immunoblot analysis showed that LCA and 1␣, 25(OH) 2-D 3 induced intracellular translocation of VDR from the cytosol to the nucleus, and also plasma membrane where VDR co-localized with caveolin-1. VDR ligands induced tyrosine phosphorylation of c-Src and VDR, and their interaction. Inhibition of c-Src abrogated VDR ligand-dependent inhibition of CYP7A1 mRNA expression. Kinase assays showed that VDR ligands specifically activated the c-Raf/MEK1/2/ERK1/2 pathway, which stimulates serine phosphorylation of VDR and HNF4␣, and their interaction. Mammalian two-hybrid assays showed a VDR ligand dependent interaction of nuclear receptor corepressor-1 (NCoR-1) and silencing mediator of retinoid and thyroid (SMRT) with VDR/RXR␣. Chromatin immunoprecipitation assays revealed that an ERK1/2 inhibitor reversed VDR ligand-induced recruitment of VDR, RXR␣ and corepressors to human CYP7A1 promoter. In conclusion, VDR ligands activate membrane VDR signaling to activate the MEK1/2/ERK1/2 pathway, which stimulates nuclear VDR/RXR␣ recruitment of co-repressors to inhibit CYP7A1 gene transcription in human hepatocytes. This membrane VDR signaling pathway may be activated by bile acids to inhibit bile acid synthesis as a rapid response to protect hepatocytes from cholestatic liver injury.
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Papers by Caterina Clementi