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Peer-reviewedCC BY 4.0Nucleic Acids Research

Genomic sequence context differentially impacts stepwise oxidation by TET enzymes to shape DNA hydroxymethylation landscapes

  • Noa Erlitzki1,2
  • Christian E Loo1
  • Johanna M Fowler2
  • Wanding Zhou3,4
  • Rahul M Kohli2
4 affiliations
  1. 1Graduate Group in Biochemistry, Biophysics, and Chemical Biology, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104 ,
  2. 2Department of Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104 ,
  3. 3Center for Computational and Genomic Medicine, The Children’s Hospital of Philadelphia , Philadelphia, PA 19104 ,
  4. 4Department of Pathology and Laboratory Medicine, University of Pennsylvania , Philadelphia, PA 19104 ,
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Abstract

Ten-eleven translocation (TET) enzymes reverse gene silencing imposed by 5-methylcytosine (5mC) in mammalian genomes by catalyzing the stepwise oxidation of 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxycytosine (5caC). 5hmC both acts as an independent epigenetic mark and promotes replication-dependent DNA demethylation by antagonizing maintenance DNA methylation. Oxidation of 5hmC to 5fC/5caC instead marks the committed step in replication-independent DNA demethylation, whereby 5fC/5caC are actively excised and reverted to unmodified cytosine. Although prior work indicates that TET-mediated oxidation is influenced by bases neighboring 5mC, these studies have been unable to resolve more than two of the relevant species—5mC, 5hmC, and 5fC/5caC—at the same time. As 5hmC is the key fulcrum in DNA demethylation, we established a high-throughput enzymology approach to probe these three cytosine states at base resolution simultaneously across hundreds of sites. We reveal distinct context dependencies for 5hmC generation versus decay, with flanking bases differentially impacting 5hmC persistence. Notably, we demonstrate these predictable preferences in duplexed DNA are lost in single-stranded DNA, mechanistically linking these features to TET-mediated base-flipping. Furthermore, analysis of genomic 5hmC patterns uncovers evidence of sequence context bias in cellular 5hmC accumulation, suggesting a role for TET-intrinsic preferences in shaping cellular epigenetic landscapes.

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Cite

BibTeXRIS
BibTeX
@article{erlitzki2026genomic,
  title = {{Genomic sequence context differentially impacts stepwise oxidation by TET enzymes to shape DNA hydroxymethylation landscapes}},
  author = {Noa Erlitzki and Christian E Loo and Johanna M Fowler and Wanding Zhou and Rahul M Kohli},
  journal = {Nucleic Acids Research},
  year = {2026},
  month = oct,
  doi = {10.1093/nar/gkag956},
  url = {https://academic.oup.com/nar/article/doi/10.1093/nar/gkag956/8913149},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Genomic sequence context differentially impacts stepwise oxidation by TET enzymes to shape DNA hydroxymethylation landscapes
AU  - Noa Erlitzki
AU  - Christian E Loo
AU  - Johanna M Fowler
AU  - Wanding Zhou
AU  - Rahul M Kohli
PY  - 2026
DA  - 2026/10/13
JO  - Nucleic Acids Research
DO  - 10.1093/nar/gkag956
UR  - https://academic.oup.com/nar/article/doi/10.1093/nar/gkag956/8913149
AB  - Ten-eleven translocation (TET) enzymes reverse gene silencing imposed by 5-methylcytosine (5mC) in mammalian genomes by catalyzing the stepwise oxidation of 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxycytosine (5caC). 5hmC both acts as an independent epigenetic mark and promotes replication-dependent DNA demethylation by antagonizing maintenance DNA methylation. Oxidation of 5hmC to 5fC/5caC instead marks the committed step in replication-independent DNA demethylation, whereby 5fC/5caC are actively excised and reverted to unmodified cytosine. Although prior work indicates that TET-mediated oxidation is influenced by bases neighboring 5mC, these studies have been unable to resolve more than two of the relevant species—5mC, 5hmC, and 5fC/5caC—at the same time. As 5hmC is the key fulcrum in DNA demethylation, we established a high-throughput enzymology approach to probe these three cytosine states at base resolution simultaneously across hundreds of sites. We reveal distinct context dependencies for 5hmC generation versus decay, with flanking bases differentially impacting 5hmC persistence. Notably, we demonstrate these predictable preferences in duplexed DNA are lost in single-stranded DNA, mechanistically linking these features to TET-mediated base-flipping. Furthermore, analysis of genomic 5hmC patterns uncovers evidence of sequence context bias in cellular 5hmC accumulation, suggesting a role for TET-intrinsic preferences in shaping cellular epigenetic landscapes.
SN  - 0305-1048
SN  - 1362-4962
ER  -