BMP-SMAD Signaling Regulates Lineage Priming, but Is Dispensable for Self-Renewal in Mouse Embryonic Stem Cells

M Gomes Fernandes, Ruben Dries, MS Roost, S Semrau, AD Bernardo, RP Davis, R Ramakrishnan, K Szuhai, E Maas, L Umans, VA Escalona, D Salvatori, D Deforce, W Van Criekinge, Danny Huylebroeck, C Mummery, A Zwijsen, SMCD Lopes

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Abstract

Naive mouse embryonic stem cells (mESCs) are in a metastable state and fluctuate between inner cell mass-and epiblast-like phenotypes. Here, we show transient activation of the BMP-SMAD signaling pathway in mESCs containing a BMP-SMAD responsive reporter transgene. Activation of the BMP-SMAD reporter transgene in naive mESCs correlated with lower levels of genomic DNA methylation, high expression of 5-methylcytosine hydroxylases Tet1/2 and low levels of DNA methyltransferases Dnmt3a/b. Moreover, naive mESCs, in which the BMP-SMAD reporter transgene was activated, showed higher resistance to differentiation. Using double Smad1; Smad5 knockout mESCs, we showed that BMP-SMAD signaling is dispensable for self-renewal in both naive and ground state. These mutant mESCs were still pluripotent, but they exhibited higher levels of DNA methylation than their wild-type counterparts and had a higher propensity to differentiate. We showed that BMP-SMAD signaling modulates lineage priming in mESCs, by transiently regulating the enzymatic machinery responsible for DNA methylation.
Original languageUndefined/Unknown
Pages (from-to)85-94
Number of pages10
JournalStem Cell Reports
Volume6
Issue number1
DOIs
Publication statusPublished - 2016

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