Epigenetic Changes Regulating Epithelial–Mesenchymal Plasticity in Human Trophoblast Differentiation
The phenotype of human placental extravillous trophoblast (EVT) at the end of pregnancy reflects both differentiation from villous cytotrophoblast (CTB) and later gestational changes, including loss of proliferative and invasive capacity. Invasion abnormalities are central to major obstetric patholo...
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2025-06-01
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| author | William E. Ackerman IV Mauricio M. Rigo Sonia C. DaSilva-Arnold Catherine Do Mariam Tariq Martha Salas Angelica Castano Stacy Zamudio Benjamin Tycko Nicholas P. Illsley |
| author_facet | William E. Ackerman IV Mauricio M. Rigo Sonia C. DaSilva-Arnold Catherine Do Mariam Tariq Martha Salas Angelica Castano Stacy Zamudio Benjamin Tycko Nicholas P. Illsley |
| author_sort | William E. Ackerman IV |
| collection | DOAJ |
| description | The phenotype of human placental extravillous trophoblast (EVT) at the end of pregnancy reflects both differentiation from villous cytotrophoblast (CTB) and later gestational changes, including loss of proliferative and invasive capacity. Invasion abnormalities are central to major obstetric pathologies, including placenta accreta spectrum, early onset preeclampsia, and fetal growth restriction. Characterization of the normal differentiation processes is, thus, essential for the analysis of these pathologies. Our gene expression analysis, employing purified human CTB and EVT cells, demonstrates a mechanism similar to the epithelial–mesenchymal transition (EMT), which underlies CTB–EVT differentiation. In parallel, DNA methylation profiling shows that CTB cells, already hypomethylated relative to non-trophoblast cell lineages, show further genome-wide hypomethylation in the transition to EVT. A small subgroup of genes undergoes gains of methylation (GOM), associated with differential gene expression (DE). Prominent in this GOM-DE group are genes involved in epithelial–mesenchymal plasticity (EMP). An exemplar is the transcription factor <i>RUNX1</i>, for which we demonstrate a functional role in regulating the migratory and invasive capacities of trophoblast cells. This analysis highlights epigenetically regulated genes acting to underpin the epithelial–mesenchymal plasticity characteristic of human trophoblast differentiation. Identification of these elements provides important information for the obstetric disorders in which these processes are dysregulated. |
| format | Article |
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| institution | DOAJ |
| issn | 2073-4409 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | MDPI AG |
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| spelling | doaj-art-3a96ad62f0604b92a44470e6a8d6f9e22025-08-20T03:17:52ZengMDPI AGCells2073-44092025-06-01141397010.3390/cells14130970Epigenetic Changes Regulating Epithelial–Mesenchymal Plasticity in Human Trophoblast DifferentiationWilliam E. Ackerman IV0Mauricio M. Rigo1Sonia C. DaSilva-Arnold2Catherine Do3Mariam Tariq4Martha Salas5Angelica Castano6Stacy Zamudio7Benjamin Tycko8Nicholas P. Illsley9Department of Obstetrics and Gynecology, Institute for Health Data Science Research, AI.Health4All Center, University of Illinois Chicago, Chicago, IL 61607, USAHackensack Meridian Health Center for Discovery and Innovation, Nutley, NJ 07110, USADepartment of Obstetrics and Gynecology, Hackensack University Medical Center, Hackensack, NJ 07601, USAHackensack Meridian Health Center for Discovery and Innovation, Nutley, NJ 07110, USAHackensack Meridian Health Center for Discovery and Innovation, Nutley, NJ 07110, USAHackensack Meridian Health Center for Discovery and Innovation, Nutley, NJ 07110, USAHackensack Meridian Health Center for Discovery and Innovation, Nutley, NJ 07110, USADepartment of Obstetrics and Gynecology, Hackensack University Medical Center, Hackensack, NJ 07601, USAHackensack Meridian Health Center for Discovery and Innovation, Nutley, NJ 07110, USADepartment of Obstetrics and Gynecology, Hackensack University Medical Center, Hackensack, NJ 07601, USAThe phenotype of human placental extravillous trophoblast (EVT) at the end of pregnancy reflects both differentiation from villous cytotrophoblast (CTB) and later gestational changes, including loss of proliferative and invasive capacity. Invasion abnormalities are central to major obstetric pathologies, including placenta accreta spectrum, early onset preeclampsia, and fetal growth restriction. Characterization of the normal differentiation processes is, thus, essential for the analysis of these pathologies. Our gene expression analysis, employing purified human CTB and EVT cells, demonstrates a mechanism similar to the epithelial–mesenchymal transition (EMT), which underlies CTB–EVT differentiation. In parallel, DNA methylation profiling shows that CTB cells, already hypomethylated relative to non-trophoblast cell lineages, show further genome-wide hypomethylation in the transition to EVT. A small subgroup of genes undergoes gains of methylation (GOM), associated with differential gene expression (DE). Prominent in this GOM-DE group are genes involved in epithelial–mesenchymal plasticity (EMP). An exemplar is the transcription factor <i>RUNX1</i>, for which we demonstrate a functional role in regulating the migratory and invasive capacities of trophoblast cells. This analysis highlights epigenetically regulated genes acting to underpin the epithelial–mesenchymal plasticity characteristic of human trophoblast differentiation. Identification of these elements provides important information for the obstetric disorders in which these processes are dysregulated.https://www.mdpi.com/2073-4409/14/13/970trophoblastdifferentiationepithelial–mesenchymal transitionDNA methylation |
| spellingShingle | William E. Ackerman IV Mauricio M. Rigo Sonia C. DaSilva-Arnold Catherine Do Mariam Tariq Martha Salas Angelica Castano Stacy Zamudio Benjamin Tycko Nicholas P. Illsley Epigenetic Changes Regulating Epithelial–Mesenchymal Plasticity in Human Trophoblast Differentiation Cells trophoblast differentiation epithelial–mesenchymal transition DNA methylation |
| title | Epigenetic Changes Regulating Epithelial–Mesenchymal Plasticity in Human Trophoblast Differentiation |
| title_full | Epigenetic Changes Regulating Epithelial–Mesenchymal Plasticity in Human Trophoblast Differentiation |
| title_fullStr | Epigenetic Changes Regulating Epithelial–Mesenchymal Plasticity in Human Trophoblast Differentiation |
| title_full_unstemmed | Epigenetic Changes Regulating Epithelial–Mesenchymal Plasticity in Human Trophoblast Differentiation |
| title_short | Epigenetic Changes Regulating Epithelial–Mesenchymal Plasticity in Human Trophoblast Differentiation |
| title_sort | epigenetic changes regulating epithelial mesenchymal plasticity in human trophoblast differentiation |
| topic | trophoblast differentiation epithelial–mesenchymal transition DNA methylation |
| url | https://www.mdpi.com/2073-4409/14/13/970 |
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