Molecular Cell
Volume 64, Issue 5, 1 December 2016, Pages 913-925
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Article
Cooperative Action between SALL4A and TET Proteins in Stepwise Oxidation of 5-Methylcytosine

https://doi.org/10.1016/j.molcel.2016.10.013Get rights and content
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Highlights

  • A SILAC-assisted DNA pull down reveals SALL4A preferentially binds 5hmC in vitro

  • SALL4A occupies enhancers in mouse ESCs, largely in a TET1-dependent manner

  • SALL4A facilitates 5hmC further oxidation at its binding sites

  • TET2 is the main enzyme catalyzing 5hmC further oxidation at SALL4A-binding sites

Summary

TET family enzymes successively oxidize 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine, leading to eventual demethylation. 5hmC and TET enzymes occupy distinct chromatin regions, suggesting unknown mechanisms controlling the fate of 5hmC within diverse chromatin environments. Here, we report that SALL4A preferentially associates with 5hmC in vitro and occupies enhancers in mouse embryonic stem cells in a largely TET1-dependent manner. Although most 5hmC at SALL4A peaks undergoes further oxidation, this process is abrogated upon deletion of Sall4 gene, with a concomitant reduction of TET2 at these regions. Thus, SALL4A facilitates further oxidation of 5hmC at its binding sites, which requires its 5hmC-binding activity and TET2, supporting a collaborative action between SALL4A and TET proteins in regulating stepwise oxidation of 5mC at enhancers. Our study identifies SALL4A as a 5hmC binder, which facilitates 5hmC oxidation by stabilizing TET2 association, thereby fine-tuning expression profiles of developmental genes in mouse embryonic stem cells.

Keywords

SALL4
TET1
TET2
DNA methylation
oxidation
enhancer

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