<i>Spic</i> regulates one-carbon metabolism and histone methylation in ground-state pluripotency.

Abstract

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-homocysteine (SAM-to-SAH), thereby, modulating the levels of H3R17me2 and H3K4me3 histone marks in ESCs. Our findings highlight betaine-dependent 1C metabolism as a hallmark of ground state pluripotency primarily activated by SPIC. These findings underscore the role of uncharacterized auxiliary TFs in linking cellular metabolism to epigenetic regulation in ESCs.