(RESEARCH PROJECT III) The establishment of pregnancy requires acquisition of key competencies within the embryo and female reproductive tract. Central to embryo competence is development of the trophoblast lineage, which represents the initial differentiation event during embryogenesis. Trophoblast cells are situated at the embryo-uterine interface and contribute fundamentally to the growth and survival of the embryo in the female reproductive tract. These vital tasks are accomplished through appropriate expansion of trophoblast stem (TS) cells and their accrual of specializations facilitating trophoblast modification of the uterine environment. Disruptions in trophoblast lineage development are associated with implantation failure, recurrent pregnancy loss, and a range of diseases affecting placentation, fetal growth, and postnatal development. Thus it is essential to understand molecular mechanisms underlying the regulation of TS cell renewal and differentiation. Transcriptional and epigenetic regulators control these fundamental processes, which are conserved across species utilizing hemochorial placentation. We have demonstrated the involvement of a defined set of histone modifications in the process of TS cell renewal and differentiation. We propose that Suv39h2, a histone H3K9 methyl transferase, and Kdm3a, a histone H3K9 demethylase, can act as a developmental switches regulating the TS cell stem state and acquisition of specialized trophoblast functions. Through chromatin modifications such as those engineered by Suv39h2 and Kdm3a networks of genes can be activated or silenced. In this project, three aims are proposed: 1) to evaluate the impact of histone H3K9 methylation machinery on TS cell renewal and differentiation;2) to identify gene networks linked to dynamic histone H3K9 methylation changes during TS cell renewal and differentiation;3) to elucidate transcription factor and co-regulator circuitry that impacts histone H3K9 methylation machinery. The investigation utilizes in vitro stem cell models and in vivo rat models to explore the role of histone H3K9 methylation in regulating the TS cell state. The proposed research provides an innovative approach to study TS cell regulation and to expand our understanding of early pregnancy loss.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
1P01HD079363-01A1
Application #
8743039
Study Section
Special Emphasis Panel (ZHD1)
Project Start
2014-07-24
Project End
2019-06-30
Budget Start
2014-07-24
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Kansas
Department
Type
DUNS #
City
Kansas City
State
KS
Country
United States
Zip Code
66160
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Aplin, John D; Beristain, Alexander; DaSilva-Arnold, Sonia et al. (2017) IFPA meeting 2016 workshop report III: Decidua-trophoblast interactions; trophoblast implantation and invasion; immunology at the maternal-fetal interface; placental inflammation. Placenta 60 Suppl 1:S15-S19
Dhakal, Pramod; Soares, Michael J (2017) Single-step PCR-based genetic sex determination of rat tissues and cells. Biotechniques 62:232-233
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Soares, Michael J; Iqbal, Khursheed; Kozai, Keisuke (2017) Hypoxia and Placental Development. Birth Defects Res 109:1309-1329
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Bu, Pengli; Alam, Sheikh M Khorshed; Dhakal, Pramod et al. (2016) A Prolactin Family Paralog Regulates Placental Adaptations to a Physiological Stressor. Biol Reprod 94:107
Imakawa, Kazuhiko; Dhakal, Pramod; Kubota, Kaiyu et al. (2016) CITED2 modulation of trophoblast cell differentiation: insights from global transcriptome analysis. Reproduction 151:509-16
Chakraborty, Damayanti; Cui, Wei; Rosario, Gracy X et al. (2016) HIF-KDM3A-MMP12 regulatory circuit ensures trophoblast plasticity and placental adaptations to hypoxia. Proc Natl Acad Sci U S A 113:E7212-E7221
Ilekis, John V; Tsilou, Ekaterini; Fisher, Susan et al. (2016) Placental origins of adverse pregnancy outcomes: potential molecular targets: an Executive Workshop Summary of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Am J Obstet Gynecol 215:S1-S46

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