Gender Differences in Global but Not Targeted Demethylation in iPSC Reprogramming.
Inês Milagre1, Thomas M Stubbs1, Michelle R King1
1Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK.
Cell Reports
|February 2, 2017
Summary
Induced pluripotent stem cell (iPSC) reprogramming involves both global and targeted DNA demethylation. These distinct processes are crucial for erasing epigenetic memory and establishing cell identity.
Area of Science:
- Epigenetics
- Stem Cell Biology
- Genomics
Background:
- DNA demethylation is essential for reprogramming in vivo and in vitro.
- The role of DNA demethylation in induced pluripotent stem cell (iPSC) derivation was previously unknown.
Purpose of the Study:
- To investigate whether DNA demethylation occurs during iPSC reprogramming.
- To determine if global and targeted demethylation are involved and if they are mechanistically separable.
Main Methods:
- Analysis of DNA methylation patterns during iPSC reprogramming.
- Investigating the role of activation-induced cytidine deaminase (AID) and UHRF1 in global demethylation.
- Examining the specific demethylation of regulatory regions associated with pluripotency genes.
Main Results:
- iPSC reprogramming involves both global and targeted DNA demethylation.
- Global demethylation is transient, occurs at intermediate-late stages, and requires AID-mediated UHRF1 downregulation.
- Targeted hypomethylation of ESC enhancers and super-enhancers occurs independently of AID and global demethylation, correlating with pluripotency gene transcription.
Conclusions:
- Global and targeted DNA demethylation are distinct, conserved processes in iPSC reprogramming.
- Global demethylation likely contributes to epigenetic memory erasure.
- Targeted demethylation is critical for establishing cell identity by activating the pluripotency network.
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