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5mC oxidation by Tet2 modulates enhancer activity and timing of transcriptome reprogramming during differentiation
Gary C Hon1, Chun-Xiao Song2, Tingting Du1
1Ludwig Institute for Cancer Research, La Jolla, CA 92093-0653, USA.
Molecular Cell
|September 30, 2014
Summary
Tet proteins regulate enhancer activity by controlling DNA demethylation. Deleting Tet2 impairs enhancer function and delays gene activation during differentiation.
Area of Science:
- Epigenetics
- Molecular Biology
- Genomics
Background:
- Cytosine methylation (5mC) is crucial for gene regulation but its role at enhancers is unclear.
- Enhancers show enrichment for 5-hydroxymethylcytosine (5hmC), a marker of DNA demethylation.
- Tet proteins are involved in dynamic DNA methylation regulation.
Purpose of the Study:
- To investigate the function of DNA demethylation at enhancers.
- To determine the role of Tet proteins in regulating enhancer activity and gene expression during differentiation.
Main Methods:
- Base-resolution mapping of DNA methylation and hydroxymethylation.
- Deletion of Tet2 in mammalian cells.
- Assessing enhancer activity and gene induction timing.
Main Results:
- Tet2 deletion led to significant loss of 5hmC at enhancers.
- Enhancers exhibited hypermethylation and reduced activity upon Tet2 deletion.
- Early gene induction during differentiation was delayed in Tet2-deficient cells.
Conclusions:
- DNA demethylation dynamically modulates enhancer activity.
- Disruption of DNA demethylation impacts the timing of transcriptome reprogramming.
- Tet proteins are critical for maintaining enhancer function and proper differentiation timing.
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