biostudies-literatureGomes Fernandes MNetherlands organization of Scientific ResearchFundação para a Ciência e TecnologiaInteruniversity Attraction PolesDutch Research Council (NWO)Scientific Research-FlandersBontius Stichting85-94https://www.ebi.ac.uk/biostudies/studies/S-EPMC4720007biostudies-literatureUnknown6(1)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.Stem cell reportsBMP-SMAD Signaling Regulates Lineage Priming, but Is Dispensable for Self-Renewal in Mouse Embryonic Stem Cells.PMC4720007ASPASIA 015.007.037015.007.037SFRH/BD/94387/2013SFRH/BD/78689/2011IUAP/PAI P7/14Van Criekinge WMaas EUmans LHuylebroeck DSzuhai KMummery CDeforce DZwijsen AGomes Fernandes MRoost MSSemrau SAbon Escalona VRamakrishnan RDries RSalvatori Dde Sousa Lopes SMde Melo Bernardo ADavis RPfalseBMP-SMAD Signaling Regulates Lineage Priming, but Is Dispensable for Self-Renewal in Mouse Embryonic Stem Cells.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.2016-01-01T00:00:00Z2016 Jan2026-05-05T11:59:18.415Z2026-04-07T21:42:32.619ZS-EPMC47200072671187510.1016/j.stemcr.2015.11.012