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<p>Understanding the interplay between DNA methylation and gene expression remains a challenge. This study explores the proteome of active DNA demethylation in murine embryonic stem cells (mESC), focusing on the base-excision-repair (BER) step initiated by the Thymine DNA Glycosylase (TDG). Using BioID2 proximity labeling, we identified a TDG interactome encompassing four functional aspects: chromatin organization and transcription, chromosomal organization, RNA processing, and ribosomal biogenesis. We show specifically that TDG participates in a genome regulatory network involving chromatin remodelers and modifiers such as RUVBL2 and the H3K4 methyltransferase complex tethering factor HCFC1, consistent with the dysregulation of histone modifications observed in TDG-deficient cells. We also identified the paraspeckle components PSPC1 and NONO as TDG interactors, implicating TDG in RNA-mediated nuclear processes. This led us to show that TDG is an RNA-binding protein, interacting with long-noncoding RNAs (lncRNA), including the paraspeckle organizing lncRNA <i>Neat1</i>, previously reported to target TET proteins to genomic sites and to engage in R-loop regulation. We then demonstrate TDG’s ability to excise oxidized 5-methylcytosine in RNA:DNA hybrids, suggesting a role of active DNA demethylation in the regulation of R-loops. Our findings thus unveil a direct crosstalk between active DNA demethylation, chromatin modification and remodeling as well as RNA-genome interactions in mESC, providing avenues for future mechanistic investigations.</p>

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The TDG protein environment connects active DNA demethylation with chromatin and RNA biology

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月25日

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  • Federica Richina,
  • Faiza Noreen,
  • Christina Bauer,
  • Alain Weber,
  • Christophe Kunz,
  • Katarzyna Buczak,
  • Simon D. Schwarz,
  • Fabian Wu,
  • David Schürmann,
  • Primo Schär

摘要

Understanding the interplay between DNA methylation and gene expression remains a challenge. This study explores the proteome of active DNA demethylation in murine embryonic stem cells (mESC), focusing on the base-excision-repair (BER) step initiated by the Thymine DNA Glycosylase (TDG). Using BioID2 proximity labeling, we identified a TDG interactome encompassing four functional aspects: chromatin organization and transcription, chromosomal organization, RNA processing, and ribosomal biogenesis. We show specifically that TDG participates in a genome regulatory network involving chromatin remodelers and modifiers such as RUVBL2 and the H3K4 methyltransferase complex tethering factor HCFC1, consistent with the dysregulation of histone modifications observed in TDG-deficient cells. We also identified the paraspeckle components PSPC1 and NONO as TDG interactors, implicating TDG in RNA-mediated nuclear processes. This led us to show that TDG is an RNA-binding protein, interacting with long-noncoding RNAs (lncRNA), including the paraspeckle organizing lncRNA Neat1, previously reported to target TET proteins to genomic sites and to engage in R-loop regulation. We then demonstrate TDG’s ability to excise oxidized 5-methylcytosine in RNA:DNA hybrids, suggesting a role of active DNA demethylation in the regulation of R-loops. Our findings thus unveil a direct crosstalk between active DNA demethylation, chromatin modification and remodeling as well as RNA-genome interactions in mESC, providing avenues for future mechanistic investigations.