The transcriptional regulatory network modulating human trophoblast stem cells to extravillous trophoblast differentiation

Mijeong Kim, Yu Jin Jang, Muyoung Lee, Qingqing Guo, Albert J. Son, Nikita A. Kakkad, Abigail B. Roland, Bum-Kyu Lee and Jonghwan Kim ()
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Mijeong Kim: The University of Texas at Austin
Yu Jin Jang: The University of Texas at Austin
Muyoung Lee: The University of Texas at Austin
Qingqing Guo: The University of Texas at Austin
Albert J. Son: The University of Texas at Austin
Nikita A. Kakkad: The University of Texas at Austin
Abigail B. Roland: The University of Texas at Austin
Bum-Kyu Lee: State University of New York
Jonghwan Kim: The University of Texas at Austin

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract During human pregnancy, extravillous trophoblasts play crucial roles in placental invasion into the maternal decidua and spiral artery remodeling. However, regulatory factors and their action mechanisms modulating human extravillous trophoblast specification have been unknown. By analyzing dynamic changes in transcriptome and enhancer profile during human trophoblast stem cell to extravillous trophoblast differentiation, we define stage-specific regulators, including an early-stage transcription factor, TFAP2C, and multiple late-stage transcription factors. Loss-of-function studies confirm the requirement of all transcription factors identified for adequate differentiation, and we reveal that the dynamic changes in the levels of TFAP2C are essential. Notably, TFAP2C pre-occupies the regulatory elements of the inactive extravillous trophoblast-active genes during the early stage of differentiation, and the late-stage transcription factors directly activate extravillous trophoblast-active genes, including themselves as differentiation further progresses, suggesting sequential actions of transcription factors assuring differentiation. Our results reveal stage-specific transcription factors and their inter-connected regulatory mechanisms modulating extravillous trophoblast differentiation, providing a framework for understanding early human placentation and placenta-related complications.

Date: 2024
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DOI: 10.1038/s41467-024-45669-2

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