2. Academic Validation
  3. Active turnover of genomic methylcytosine in pluripotent cells

Active turnover of genomic methylcytosine in pluripotent cells

  • Nat Chem Biol. 2020 Dec;16(12):1411-1419. doi: 10.1038/s41589-020-0621-y.
Fabio Spada 1,  Sarah Schiffers 2 3,  Angie Kirchner 2 4,  Yingqian Zhang 2 5,  Gautier Arista 2,  Olesea Kosmatchev 2,  Eva Korytiakova 2,  René Rahimoff 2 6,  Charlotte Ebert 2,  Thomas Carell 7
Affiliations

Affiliations

  • 1 Department of Chemistry, Ludwig Maximilians University Munich and Center for Integrated Protein Science Munich (CIPSM), Munich, Germany. [email protected].
  • 2 Department of Chemistry, Ludwig Maximilians University Munich and Center for Integrated Protein Science Munich (CIPSM), Munich, Germany.
  • 3 National Cancer Institute, Center for Cancer Research, Bethesda, MD, USA.
  • 4 Cancer Research UK Cambridge Institute, Cambridge, UK.
  • 5 State Key Laboratory of Elemento-organic Chemistry and Department of Chemical Biology, College of Chemistry, Nankai University, Tianjin, China.
  • 6 Department of Chemistry, University of California, Los Angeles, Berkeley, CA, USA.
  • 7 Department of Chemistry, Ludwig Maximilians University Munich and Center for Integrated Protein Science Munich (CIPSM), Munich, Germany. [email protected].
PMID: 32778844 DOI: 10.1038/s41589-020-0621-y
Abstract

Epigenetic plasticity underpins cell potency, but the extent to which active turnover of DNA methylation contributes to such plasticity is not known, and the underlying pathways are poorly understood. Here we use metabolic labeling with stable isotopes and mass spectrometry to quantitatively address the global turnover of genomic 5-methyl-2'-deoxycytidine (mdC), 5-hydroxymethyl-2'-deoxycytidine (hmdC) and 5-formyl-2'-deoxycytidine (fdC) across mouse pluripotent cell states. High rates of mdC/hmdC oxidation and fdC turnover characterize a formative-like pluripotent state. In primed pluripotent cells, the global mdC turnover rate is about 3-6% faster than can be explained by passive dilution through DNA synthesis. While this active component is largely dependent on ten-eleven translocation (Tet)-mediated mdC oxidation, we unveil additional oxidation-independent mdC turnover, possibly through DNA repair. This process accelerates upon acquisition of primed pluripotency and returns to low levels in lineage-committed cells. Thus, in pluripotent cells, active mdC turnover involves both mdC oxidation-dependent and oxidation-independent processes.

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