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02.03.17 Identifying genes resistant to reprogramming and how epigenetic pathways are involved

last modified Mar 16, 2017 04:34 PM
Performing nuclear transfer of mouse ES cells and fibroblasts allowed the Gurdon lab with international colleagues to identify genes that resist reprogramming
02.03.17 Identifying genes resistant to reprogramming and how epigenetic pathways are involved

Artwork by Ethan Tyler, NIH Medical Arts

Gene Resistance to Transcriptional Reprogramming following Nuclear Transfer Is Directly Mediated by Multiple Chromatin-Repressive Pathways

Jullien J et al. (2017) Molecular Cell doi: 10.1016/j.molcel.2017.01.030.

 

Highlights and summary from the paper

• Identification of genes resistant to direct transcriptional reprogramming
• Determination of resistant gene sensitivity to 11 chromatin modifier combinations
• USP21 removes resistance through its H2AK119 deubiquitylation activity
• USP21 improves the reprogramming of gene expression in two-cell-stage mouse embryos


Understanding the mechanism of resistance of genes to reactivation will help improve the success of nuclear reprogramming. Using mouse embryonic fibroblast nuclei with normal or reduced DNA methylation in combination with chromatin modifiers able to erase H3K9me3, H3K27me3, and H2AK119ub1 from transplanted nuclei, we reveal the basis for resistance of genes to transcriptional reprogramming by oocyte factors.

A majority of genes is affected by more than one type of treatment, suggesting that resistance can require repression through multiple epigenetic mechanisms. We classify resistant genes according to their sensitivity to 11 chromatin modifier combinations, revealing the existence of synergistic as well as adverse effects of chromatin modifiers on removal of resistance.

We further demonstrate that the chromatin modifier USP21 reduces resistance through its H2AK119 deubiquitylation activity. Finally, we provide evidence that H2A ubiquitylation also contributes to resistance to transcriptional reprogramming in mouse nuclear transfer embryos.

 

Read more about research in the Gurdon lab.

Studying development to understand disease

The Gurdon Institute is funded by Wellcome and Cancer Research UK to study the biology of development, and how normal growth and maintenance go wrong in cancer and other diseases.

 

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