We propose testing the hypothesis that shifts in the human cytotrophoblast (CTB) epigenome early in pregnancy are integral to their normal differentiation, formation of the placenta and pregnancy success. CTB fate decisions establish placental structure and thereby function. In one pathway, CTBs fuse to form the syncytiotrophoblasts (STBs) that cover the surface of chorionic villi. These cells produce hormones and exchange myriad substances between the mother and the embryo/fetus. In the other differentiation pathway, CTBs emigrate from the chorionic villi and invade the uterus, anchoring the placenta to the mother. In the process, they tap into the resident arteries and veins, establishing blood flow to the intervillous space. Recently we employed sequencing approaches to profile the CTB epigenome in late 2nd trimester and at term. The data revealed a unique pattern of global hypomethylation punctuated by megabase domains of even deeper valleys of hypomethylation. In comparison, other human embryonic, fetal, and adult genomes were highly methylated. Unexpectedly, H3K9me3 occupancy precisely overlapped domains with more pronounced DNA hypomethylation and repressed transcription. Also, we discovered significant gestational age-related alterations in the CTB epigenome. During the late 2nd trimester-to-term interval, substantial genome-wide increases in DNA methylation were accompanied by depletion of H3K9me3 and H3K4me. Surprisingly, we also found changes in histone abundance at the end of the 1st trimester, i.e., a substantial decrease in H3K27me3 and H3K4me1 signals. Work from other investigators suggests parallel increases in DNA methylation of placental promoters over the same period. Thus, the CTB epigenome appears to be evolving throughout pregnancy with significant changes early as well as later in gestation. To understand the functional consequences of these shifts, we propose two Specific Aims. First, we will investigate the relationship between alterations in the CTB epigenome and transcriptome at the end of the 1st trimester of pregnancy. Changes in DNA methylation and key histone modification profiles will be intersected with expression data to identify pathways and their drivers that are modulated. Second, we will test the functional significance of the drivers in our in vitro models of CTB differentiation, which enable interrogating formation of STBs or invasive extravillous CTBs. The most innovative aspect of this project is the intent to build on our recent discovery of the unique nature of the human CTB epigenome, which exhibits substantial shifts over gestation. The significance lies in the importance of CTB differentiation to placental development and function. Our goal is to achieve a new level of understanding about the mechanisms that are involved, information that has translational value in terms of gaining new insights into failures in these processes. We reason that they may be associated with some cases of infertility and 1st trimester losses or lie at the root of pregnancy complications associated with faulty placentation, e.g., preeclampsia intrauterine growth restriction.

Public Health Relevance

In recently completed experiments, we profiled the epigenome of cytotrophoblasts, progenitors that differentiate into the placenta's specialized cells. We discovered that the cytotrophoblast epigenome has a unique signature that undergoes substantial shifts over gestation. Here we propose experiments to understand the functional consequences of epigenetic changes at the end of the first trimester, which we theorize are key to a successful pregnancy. Conversely, defects may be associated with placental pathologies, which could contribute to infertility, early pregnancy losses or complications later on that are associated with aberrant cytotrophoblast differentiation, e.g., preeclampsia.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center (P50)
Project #
5P50HD055764-13
Application #
9908142
Study Section
Special Emphasis Panel (ZHD1)
Project Start
Project End
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
13
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
Barnhart, Kurt; Giudice, Linda; Young, Steve et al. (2018) Evaluation, validation and refinement of noninvasive diagnostic biomarkers for endometriosis (ENDOmarker): A protocol to phenotype bio-specimens for discovery and validation. Contemp Clin Trials 68:1-6
Conti, Marco; Franciosi, Federica (2018) Acquisition of oocyte competence to develop as an embryo: integrated nuclear and cytoplasmic events. Hum Reprod Update 24:245-266
Martin, Jeremy W; Chen, Joseph C; Neidleman, Jason et al. (2018) Potent and rapid activation of tropomyosin-receptor kinase A in endometrial stromal fibroblasts by seminal plasma. Biol Reprod 99:336-348
Logan, Philip C; Yango, Pamela; Tran, Nam D (2018) Endometrial Stromal and Epithelial Cells Exhibit Unique Aberrant Molecular Defects in Patients With Endometriosis. Reprod Sci 25:140-159
Aghajanova, Lusine; Houshdaran, Sahar; Balayan, Shaina et al. (2018) In vitro evidence that platelet-rich plasma stimulates cellular processes involved in endometrial regeneration. J Assist Reprod Genet 35:757-770
Freimer, Jacob W; Krishnakumar, Raga; Cook, Matthew S et al. (2018) Expression of Alternative Ago2 Isoform Associated with Loss of microRNA-Driven Translational Repression in Mouse Oocytes. Curr Biol 28:296-302.e3
Roan, Nadia R; Sandi-Monroy, Nathallie; Kohgadai, Nargis et al. (2017) Semen amyloids participate in spermatozoa selection and clearance. Elife 6:
Rinaudo, Paolo F; Conti, Marco (2017) Report from the 2016 University of California, San Francisco, Center for Reproductive Sciences retreat. Mol Reprod Dev 84:1024-1026
Paikari, Alireza; D Belair, Cassandra; Saw, Daniel et al. (2017) The eutheria-specific miR-290 cluster modulates placental growth and maternal-fetal transport. Development 144:3731-3743
Aghajanova, Lusine; Houshdaran, Sahar; Irwin, Juan C et al. (2017) Effects of noncavity-distorting fibroids on endometrial gene expression and function. Biol Reprod 97:564-576

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