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Reprogramming by De-bookmarking the Somatic Transcriptional Program through Targeting of BET Bromodomains
Zhicheng Shao1, Chunping Yao2, Alireza Khodadadi-Jamayran1
1Stem Cell Institute, Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294-0024, USA.
Cell Reports
|September 23, 2016
Summary
Small molecules targeting BET bromodomains, crucial for transcriptional memory, enhance cell reprogramming to pluripotency. This strategy effectively erases somatic cell identity, facilitating cell fate conversion.
Area of Science:
- Stem cell biology
- Epigenetics
- Molecular biology
Background:
- Cellular reprogramming to pluripotency requires erasing the original somatic cell's transcriptional program.
- Transcriptional memory, maintained by mechanisms like somatic transcriptional bookmarking, poses a barrier to efficient reprogramming.
- BET bromodomains are identified as key transcriptional bookmarking domains involved in maintaining cell identity.
Purpose of the Study:
- To present a novel strategy for enhancing reprogramming to pluripotency using small molecules.
- To investigate the role of BET bromodomains in maintaining somatic transcriptional memory during reprogramming.
- To demonstrate the efficacy of targeting BET bromodomains for cell fate conversion.
Main Methods:
- Utilizing small molecules to chemically target the acetyllysine-binding pockets of BET bromodomains.
- Assessing the impact of BET bromodomain inhibition on somatic gene expression in fibroblasts.
- Observing morphological changes in cells undergoing reprogramming with BET bromodomain inhibitors.
Main Results:
- Mild chemical targeting of BET bromodomains significantly enhances reprogramming efficiency.
- Inhibition of BET bromodomains downregulates or silences somatic gene expression.
- Chemical blocking of BET bromodomains leads to early loss of fibroblast morphology.
Conclusions:
- Targeting transcriptional bookmarking BET bromodomains is a viable strategy to overcome somatic transcriptional memory.
- Chemical intervention in BET bromodomain function facilitates robust cell fate conversion towards pluripotency.
- This approach offers a new avenue for improving reprogramming technologies.
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