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. 2022 Aug 9;11(16):2466. doi: 10.3390/cells11162466

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© 2022 by the authors.

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

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CGI hypomethylation licenses trophoblast differentiation-promoting genes for precocious up-regulation. (A) Expression dynamics of trophoblast differentiation-relevant genes that are associated with hypomethylated CGIs in Padi2/3 DKO cells across a TSC differentiation time course. (B) Immunofluorescence staining for PEG3 indicates its up-regulation in TSCs after 3 days of differentiation. (C) RT-qPCR analysis showing the up-regulation of genes associated with hypomethylated CGIs (Gata3_202, 9230102O04Rik, Hand1) and TGC differentiation markers (Prl2c2, Prl3d1) in Padi2/3 DKO TSCs under stem cell conditions. Data are expressed relative to WT TSCs and are displayed as the mean +/− S.E.M. Statistical analysis by unpaired Student’s t-test (* p < 0.05; ** p < 0.01; n = 4 independent clones per genotype). (D) Immunofluorescence staining for PEG3 showing stronger expression in the enlarged TGCs (arrow) that are evident in Padid2/3 DKO TSCs under stem cell conditions. (E) Immunostaining for FLAG-tagged PADI3 in TSCs revealing unequivocally nuclear localization (arrows) in TSCs. (F) Model depicting the role of PADI2/3 in TSCs. Both PADIs act synergistically to prevent precocious TGC differentiation by maintaining DNA methylation at CGIs that are associated with key trophoblast genes, preventing their premature up-regulation. This inhibitory effect towards TGC formation allows for the sufficient differentiation of SynT cells.