The earliest known step in mammalian development is the formation of the trophoblast from the totipotential embryonic stem cell. The subsequent differentiation of the trophoblast stem cells (TS) to the placental syncytiotrophoblast (SynT) establishes the epithelial interface between fetal and maternal circulatory systems, mediating essential nutrient exchange and oxygen transport. The SynT also serves as the primary site of fetal hormone production that conditions maternal and fetal systems to sustain a successful gestation. The major hormones synthesized in the SynT are chorionic somatomammotropin (hCS) and growth hormone-variant (hGH-V). Both hormones are encoded in the multi-gene human growth hormone (hGH) gene cluster that also encompasses the pituitary growth hormone gene, hGH-N. We hypothesize that the selective and robust activation of the placental hCS and hGH-V genes during differentiation of TS to SynT reflects a defined progression of epigenetic modifications and alterations in chromatin structures that distinguish this pathway from that involved in activation of hGH-N in pituitary somatotropes. We further hypothesize that this developmental progression reflects global epigenetic controls that are fundamental to SynT differentiation and distinguish this lineage from the TS-derived lineage that leads to the formation of invasive trophoblast cells. The selective activation of the placentally-expressed genes from the hGH cluster thus presents an optimal model for understanding mechanisms of gene activation that underlie TS cell differentiation and that define function(s) of SynT cells in the placenta. Our proposal will address five Specific Aims: I. Establish mouse TS lines that model activation of the hGH locus during SynT differentiation. II. Define the structural alterations at the hGH locus that coincide with SynT-lineage commitment and the subsequent transcriptional induction of the hCS/hGH-V genes. III. Establish mechanistic linkages between SynT differentiation and hGH locus activation. IV. Identify structural features of the hGH locus required for activation in SynT. V. Define higher-order conformations at the hGH chromatin locus in SynT necessary for placenta-specific gene activation. These studies should expand our understanding of placental gene expression and development and expand our insights into the corresponding defects that impact on maternal and fetal health during gestation.

Public Health Relevance

A normally developed and functioning placenta is critical to gestation. It is responsible for essential nutrient exchange and oxygen transport between mother and fetus and is a major source of fetal hormone production. This project will study specific questions regarding the development and function of the human placenta, in some cases using transgenic mouse models. These studies are expected expand our understanding maternal and fetal health during gestation.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Pregnancy and Neonatology Study Section (PN)
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Ilekis, John V
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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Tsai, Yu-Cheng; Cooke, Nancy E; Liebhaber, Stephen A (2014) Tissue specific CTCF occupancy and boundary function at the human growth hormone locus. Nucleic Acids Res 42:4906-21
Ho, Yugong; Shewchuk, Brian M; Liebhaber, Stephen A et al. (2013) Distinct chromatin configurations regulate the initiation and the maintenance of hGH gene expression. Mol Cell Biol 33:1723-34
Ho, Yugong; Liebhaber, Stephen A; Cooke, Nancy E (2011) The role of the hGH locus control region in somatotrope restriction of hGH-N gene expression. Mol Endocrinol 25:877-84
Sizova, Daria; Ho, Yugong; Cooke, Nancy E et al. (2010) Research resource: T-antigen transformation of pituitary cells captures three novel cell lines in the Pit-1 lineage. Mol Endocrinol 24:2232-40
Ho, Yugong; Tadevosyan, Aleksey; Liebhaber, Stephen A et al. (2008) The juxtaposition of a promoter with a locus control region transcriptional domain activates gene expression. EMBO Rep 9:891-8
Kimura, Atsushi P; Sizova, Daria; Handwerger, Stuart et al. (2007) Epigenetic activation of the human growth hormone gene cluster during placental cytotrophoblast differentiation. Mol Cell Biol 27:6555-68
Yoo, Eung Jae; Cajiao, Isabela; Kim, Jeong-Seon et al. (2006) Tissue-specific chromatin modifications at a multigene locus generate asymmetric transcriptional interactions. Mol Cell Biol 26:5569-79