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New TET2 Research Describes a New Chromatin-Regulation Pathway and a Novel Cancer Target

By Stuart P. Atkinson, Ph.D.

June 11, 2026

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The Unexpected Epigenetic Consequences of TET2 Loss: Can Chromatin-associated RNAs Provide an Explanation?

The TET methylcytosine dioxygenase enzymes (TET1-3) help to regulate gene expression by promoting DNA demethylation and creating a permissive chromatin landscape that supports gene expression (Zhang et al.). Interestingly, TET2 loss-of-function results in a reduction rather than the expected increase in DNA methylation (Figueroa et al.) and a global opening of the chromatin landscape (Moran-Crusio et al. and Lopez-Moyado et al.). Overall, these findings suggested that certain functional outcomes associated with TET2-deficiency may function through a pathway distinct from the regulation of DNA methylation.

Interestingly, a range of recent studies has provided evidence that TET2 can also promote the oxidation of RNA 5-methylcytosine (m5C), a modification that modulates RNA stability, translation, transcription, and nuclear export, thereby influencing a huge range of biological functions. Researchers led by Mingjiang Xu (University of Texas Health Science Center at San Antonio) and Chuan He (The University of Chicago) and others had previously reported that RNA N6-methyladenosine modification dynamics on chromatin-associated RNAs contributed to local and global chromatin regulation during mouse early embryo development and cancer progression (Xu et al., Liu et al. 2021, Chelmicki et al., Liu et al. 2020, and Wei et al.). N6-methyladenosine represents a prevalent and extensively studied RNA modification that influences RNA folding, stability, and protein interactions; meanwhile, retained cis-acting or recruited trans-acting chromatin-associated RNAs play diverse roles in gene regulation and genome function, including locus-specific roles in gene activation/silencing and higher-order genome organization.

Now, a new study from the Xu and He labs explored the possible implication of TET2-mediated chromatin-associated RNA m5C oxidation in chromatin regulation (Zou, Dou, and Li et al.); now, their fascinating new Nature study describes a TET2-driven chromatin-regulation pathway and highlights the methyl-CpG-binding-domain protein MBD6 as a potentially exciting therapeutic target for TET2-mutant cancers.

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TET2 Loss Increases m5C chromatin-associated RNA levels, MBD6 Recruitment, and H2AK119ub Deubiquitination

The authors first evaluated the distribution of DNA hypomethylation and hypermethylation across the genome in mouse embryonic stem cells lacking TET2. Interestingly, they found DNA hypermethylation (as expected from the loss of the TET2 DNA demethylase) at gene enhancer elements, which would inhibit regulatory activity and decrease target gene expression; however, of greater interest, they observed DNA hypomethylation at repetitive elements (which play critical roles in driving evolution, inducing variation, and regulating gene expression) in the same cells, which would promote an open chromatin landscape supportive of RNA transcription.

The study went on to demonstrate TET2's ability to oxidize m5C methylation on chromatin-associated RNAs derived from these repetitive elements (including long terminal repeats [LTRs] and long interspersed nuclear elements [LINEs]). They also discovered that MBD6 (in addition to MBD5) preferentially recognized m5C-modified chromatin-associated RNAs produced from repeat elements and supported the recruitment of a polycomb repressive deubiquitylase (PR-DUB) complex to promote H2AK119ub deubiquitination of chromatin and, as such, install a global open chromatin state that would support gene transcription.

In normal cells, the presence of TET2 would support the oxidation of m5C-modified repeat RNA, thereby inhibiting target gene transcription by preventing MBD6 recruitment, inhibiting H2AK119ub deubiquitination, and allowing the accumulation of this repressive histone modification (associated with DNA hypermethylation). Meanwhile, in cancer cells, the loss of TET2 function leads to the m5C hypermethylation of chromatin-associated RNAs, which promotes MBD6 binding and H2AK119ub deubiquitination, resulting in a more open chromatin state (associated with DNA hypomethylation) and the potential transcription of cancer-associated genes. Of significant note, the authors found that MBD6 depletion selectively blocked the proliferation of TET2-mutant leukemic cells and largely reversed associated hematopoietic defects in mouse models, suggesting a potential therapeutic option for this type of cancer.

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A New Chromatin-Regulation Pathway and a Novel Therapeutic Target for TET2-Mutant Cancers

While this fascinating new Nature study describes a TET2-driven chromatin-regulation pathway and highlights MBD6 as a potential therapeutic target for TET2-mutant cancers, the authors do note the need for additional research, including an analysis of whether the m5C oxidation product (5-hydroxymethylcytosine; hm5C) further promotes chromatin-associated RNA degradation.

Of note, this exciting study employed a range of Active Motif products, which included the ATAC–seq kit, CUT&Tag-IT Assay Kit, ATAC-Seq Spike-In Control (to overcome variation between ATAC-Seq datasets), ChIP-Seq Spike-In Normalization (to compare ChIP-seq datasets with confidence), and recombinant Tn5 transposase; additional relevant products include TET antibodies and recombinant proteins. How can Active Motif help your cancer epigenetics study?

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About the author

Stuart P. Atkinson, Ph.D.

Stuart was born and grew up in the idyllic town of Lanark (Scotland). He later studied biochemistry at the University of Strathclyde in Glasgow (Scotland) before gaining his Ph.D. in medical oncology; his thesis described the epigenetic regulation of the telomerase gene promoters in cancer cells. Following Post-doctoral stays in Newcastle (England) and Valencia (Spain) where his varied research aims included the exploration of epigenetics in embryonic and induced pluripotent stem cells, Stuart moved into project management and scientific writing/editing where his current interests include polymer chemistry, cancer research, regenerative medicine, and epigenetics. While not glued to his laptop, Stuart enjoys exploring the Spanish mountains and coastlines (and everywhere in between) and the food and drink that it provides!

Contact Stuart on X with any questions

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