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Epigenetic reprogramming by TET enzymes impacts co-transcriptional R-loops.

João C Sabino1, Madalena R de Almeida1, Patrícia L Abreu1

  • 1Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.

Elife
|February 22, 2022
PubMed
Summary
This summary is machine-generated.

Ten-eleven translocation (TET) enzyme activity drives epigenetic reprogramming by promoting R-loop formation. This DNA oxidation mechanism influences gene expression during stem cell development.

Keywords:
DNA hydroxymethylationR-loopsTET enzymeschromosomesgene expressionhumanmousestem cells

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Area of Science:

  • Epigenetics
  • Molecular Biology
  • Genetics

Background:

  • Ten-eleven translocation (TET) enzymes are crucial for epigenetic reprogramming.
  • TET-mediated oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) initiates cell-type-specific transcription.
  • 5hmC influences chromatin structure and gene expression.

Purpose of the Study:

  • To investigate the role of 5hmC in R-loop formation.
  • To elucidate the mechanisms by which TET activity regulates gene expression.
  • To explore the connection between epigenetic reprogramming and R-loop dynamics.

Main Methods:

  • Depletion of TET enzymes.
  • CRISPR-mediated tethering of TET to active genes.
  • Genome-wide analysis of 5hmC and R-loop distribution.
  • Analysis of gene expression changes upon R-loop resolution.

Main Results:

  • 5hmC presence in transcribed genes promotes R-loop formation.
  • TET enzyme depletion reduces global R-loops; TET tethering promotes R-loops.
  • A positive correlation exists between 5hmC and R-loop genome-wide distribution in stem cells.
  • R-loop resolution affects the expression of genes critical for stem cell proliferation.

Conclusions:

  • TET-mediated epigenetic reprogramming promotes co-transcriptional R-loop formation.
  • This process reveals novel mechanisms for gene expression regulation.
  • R-loops play a significant role in stem cell proliferation and development.