Reprogramming by de-bookmarking somatic transcriptional program via targeting the BET bromodomains

One critical task in pluripotent reprogramming is to erase the somatic transcriptional program of starting cells. No strategy or theory exists for achieving erasure of somatic gene expression memory. Here, we present a proof-of-principle strategy in which reprogramming to pluripotency is facilitated by small molecules that erase somatic cell transcription 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 dramatically downregulates specific somatic gene expression programs in both naïve and reprogramming fibroblasts. Chemical blocking of the BET bromodomains also resulted in loss of fibroblast morphology early in reprograming. In this study, we experimentally demonstrate a concept for cell fate conversion: facilitating the conversion by chemically targeting the transcriptional bookmarking BET bromodomains responsible for transcriptional memory. Overall design: human BJ cells were treated with JQ1 at 50 nM for 48 hours. Differential expression was compared with DMSO treatment. The same treatments and comparsion were conducted for reprogramming BJ cells, which were transduced with OCT4, SOX2, and KLF4. JQ1iPSC5 is a iPSC (induced pluripotent stem cell) line generated in this study using small molecules JQ1.

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Shao Z, Yao C, Khodadadi-Jamayran A, Xu W, Townes TM, Crowley MR, Hu K