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Editing DNA methylation in vivo.

Richard Pan1, Jingwei Ren1, Xinyue Chen1

  • 1Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, Columbia University, New York City, NY, USA.

Nature Communications
|December 10, 2025
PubMed
Summary
This summary is machine-generated.

Researchers developed new mouse models for precise in vivo DNA methylation editing. This technique successfully altered gene expression, impacting cholesterol levels and rescuing neurological conditions, showing promise for epigenetic research.

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Area of Science:

  • Epigenetics
  • Molecular Biology
  • Genetics

Background:

  • DNA methylation is a key epigenetic regulator of gene expression.
  • Current DNA methylation editing tools are largely limited to in vitro applications due to delivery challenges.

Purpose of the Study:

  • To develop and validate a system for inducible, tissue-specific DNA methylation editing in vivo.
  • To demonstrate the functional consequences of targeted DNA methylation and demethylation in living organisms.

Main Methods:

  • Generation of transgenic mouse lines expressing inducible dCas9-DNMT3A (for methylation) and dCas9-TET1 (for demethylation) editors.
  • Targeted epigenetic editing of specific gene promoters (Psck9 and Mecp2) in vivo.
  • Assessment of gene expression changes, physiological outcomes (serum cholesterol, neuronal morphology), and genome-wide off-target effects via sequencing.

Main Results:

  • Targeted methylation of the Psck9 promoter in dCas9-DNMT3A mice reduced Pcsk9 expression and lowered serum LDL cholesterol.
  • Targeted demethylation of the Mecp2 promoter in dCas9-TET1 mice reactivated X-chromosome expression and rescued neuronal defects in Mecp2+/- mice.
  • Genome-wide analyses confirmed minimal transcriptional off-target effects, highlighting the system's specificity.

Conclusions:

  • The developed inducible dCas9-based editors enable precise and tissue-specific DNA methylation editing in vivo.
  • This technology provides a versatile platform for interrogating the functional roles of DNA methylation in complex biological processes and disease models.