Reprogramming by De-bookmarking the Somatic Transcriptional Program through Targeting of BET Bromodomains

Zhicheng Shao, Chunping Yao, Alireza Khodadadi-Jamayran, Weihua Xu, Tim M. Townes, Michael R. Crowley, Kejin Hu

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

One critical event in reprogramming to pluripotency is erasure of the somatic transcriptional program of starting cells. Here, we present the proof of principle of a strategy for reprogramming to pluripotency facilitated by small molecules that interfere with the somatic transcriptional memory. We show that mild chemical targeting of the acetyllysine-binding pockets of the BET bromodomains, the transcriptional bookmarking domains, robustly enhances reprogramming. Furthermore, we show that chemical targeting of the transcriptional bookmarking BET bromodomains downregulates or turns off the expression of somatic genes in both naive and reprogramming fibroblasts. Chemical blocking of the BET bromodomains also results in loss of fibroblast morphology early in reprogramming. We therefore experimentally demonstrate that cell fate conversion can be achieved by chemically targeting the transcriptional bookmarking BET bromodomains responsible for transcriptional memory.

Original languageEnglish
Pages (from-to)3138-3145
Number of pages8
JournalCell Reports
Volume16
Issue number12
DOIs
StatePublished - 20 Sep 2016

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