Human Trophoblast Differentiation Is Associated With Profound Gene Regulatory and Epigenetic Changes
| Autor: | Youn Tae Kwak, Carole R. Mendelson, Sribalasubashini Muralimanoharan, Aishwarya A. Gogate |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Placenta Cellular differentiation RNA polymerase II Epigenesis Genetic Cell Fusion Histones 03 medical and health sciences 0302 clinical medicine Endocrinology Pregnancy Internal medicine Gene expression Nuclear Receptor Subfamily 4 Group A Member 1 medicine Humans Epigenetics Promoter Regions Genetic Transcription factor Cells Cultured Research Articles Regulation of gene expression biology Trophoblast Cell Differentiation Promoter Trophoblasts Cell biology 030104 developmental biology medicine.anatomical_structure Gene Expression Regulation 030220 oncology & carcinogenesis biology.protein Female RNA Polymerase II |
| Zdroj: | Endocrinology |
| ISSN: | 1945-7170 |
| Popis: | Defective placental implantation and vascularization with accompanying hypoxia contribute to preeclampsia (PE), a leading cause of maternal and neonatal morbidity and mortality. Genetic and epigenetic mechanisms underlying differentiation of proliferative cytotrophoblasts (CytTs) to multinucleated syncytiotrophoblast (SynT) are incompletely defined. The SynT performs key functions in nutrient and gas exchange, hormone production, and protection of the fetus from rejection by the maternal immune system. In this study, we used chromatin immunoprecipitation sequencing of midgestation human trophoblasts before CytT and after SynT differentiation in primary culture to analyze changes in binding of RNA polymerase II (Pol II) and of active and repressive histone marks during SynT differentiation. Our findings reveal that increased Pol II binding to promoters of a subset of genes during trophoblast differentiation was closely correlated with active histone marks. This gene set was enriched in those controlling immune response and immune modulation, including interferon-induced tetratricopeptide repeat and placenta-specific glycoprotein gene family members. By contrast, genes downregulated during SynT differentiation included proinflammatory transcription factors ERG1, cFOS, and cJUN, as well as members of the NR4A orphan nuclear receptor subfamily, NUR77, NURR1, and NOR1. Downregulation of proinflammatory transcription factors upon SynT differentiation was associated with decreased promoter enrichment of endogenous H3K27Ac and H3K9Ac and enhanced binding of H3K9me3 and histone deacetylase 1. However, promoter enrichment of H3K27me3 was low in both CytT and SynT and was not altered with changes in gene expression. These findings provide important insight into mechanisms underlying human trophoblast differentiation and may identify therapeutic targets for placental disorders, such as PE. |
| Databáze: | OpenAIRE |
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