biostudies-literatureMirzadeh Azad FMedical Research Councileadg7997https://www.ebi.ac.uk/biostudies/studies/S-EPMC11801372biostudies-literatureUnknown9(33)Understanding mechanisms of epigenetic regulation in embryonic stem cells (ESCs) is of fundamental importance for stem cell and developmental biology. Here, we identify <i>Spic</i>, a member of the ETS family of transcription factors (TFs), as a marker of ground state pluripotency. We show that <i>Spic</i> is rapidly induced in ground state ESCs and in response to extracellular signal-regulated kinase (ERK) inhibition. We find that SPIC binds to enhancer elements and stabilizes NANOG binding to chromatin, particularly at genes involved in choline/one-carbon (1C) metabolism such as <i>Bhmt</i>, <i>Bhmt2</i>, and <i>Dmgdh</i>. Gain-of-function and loss-of-function experiments revealed that <i>Spic</i> controls 1C metabolism and the flux of <i>S</i>-adenosyl methionine to <i>S</i>-adenosyl-L-Science advances<i>Spic</i> regulates one-carbon metabolism and histone methylation in ground-state pluripotency.PMC11801372MR/X008517/1Wingert VAtlasi YMills KStunnenberg HGLongley DBMirzadeh Azad FStruys EAHannibal LJansen JHfalse<i>Spic</i> regulates one-carbon metabolism and histone methylation in ground-state pluripotency.Understanding mechanisms of epigenetic regulation in embryonic stem cells (ESCs) is of fundamental importance for stem cell and developmental biology. Here, we identify <i>Spic</i>, a member of the ETS family of transcription factors (TFs), as a marker of ground state pluripotency. We show that <i>Spic</i> is rapidly induced in ground state ESCs and in response to extracellular signal-regulated kinase (ERK) inhibition. We find that SPIC binds to enhancer elements and stabilizes NANOG binding to chromatin, particularly at genes involved in choline/one-carbon (1C) metabolism such as <i>Bhmt</i>, <i>Bhmt2</i>, and <i>Dmgdh</i>. Gain-of-function and loss-of-function experiments revealed that <i>Spic</i> controls 1C metabolism and the flux of <i>S</i>-adenosyl methionine to <i>S</i>-adenosyl-L-2023-01-01T00:00:00Z2023 Aug2025-04-04T23:59:41.743Z2025-04-04T23:59:41.743ZS-EPMC118013723759503410.1126/sciadv.adg7997