Shao Zhicheng, Yao Chunping, Khodadadi-Jamayran Alireza, Xu Weihua, Townes Tim M, Crowley Michael R, Hu Kejin
Stem Cell Institute, Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294-0024, USA.
Stem Cell Institute, Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294-0024, USA; Department of Radiation Oncology, Shandong Cancer Hospital, Shandong University, Jinan, Shandong 250117, China.
Cell Rep. 2016 Sep 20;16(12):3138-3145. doi: 10.1016/j.celrep.2016.08.060.
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.
重编程为多能性的一个关键事件是起始细胞的体细胞转录程序的消除。在此，我们展示了一种由干扰体细胞转录记忆的小分子促进重编程为多能性策略的原理证明。我们表明，对BET溴结构域（转录书签结构域）的乙酰赖氨酸结合口袋进行温和化学靶向，能有力地增强重编程。此外，我们表明，对转录书签BET溴结构域进行化学靶向可下调或关闭幼稚和成纤维细胞重编程过程中体细胞基因的表达。对BET溴结构域的化学阻断还会在重编程早期导致成纤维细胞形态丧失。因此，我们通过实验证明，通过化学靶向负责转录记忆的转录书签BET溴结构域可以实现细胞命运转换。
