Isoform-specific involvement of Brpf1 in expansion of adult hematopoietic stem and progenitor cells  

作　　者：Qiuping He Mengzhi Hong Jincan He Weixin Chen Meng Zhao Wei Zhao 

机构地区：[1]RNA Biomedical Institute,Sun Yat-sen Memorial Hospital,Sun Yat-sen University,Guangzhou 510120,China [2]Key Laboratory of Stem Cells and Tissue Engineering,Sun Yat-sen University,Ministry of Education,Guangzhou 510080,China

出　　处：《Journal of Molecular Cell Biology》2020年第5期359-371,共13页分子细胞生物学报（英文版）

基　　金：supported by National Key Research and Development Program of China(2017YFA0103802);the National Natural Science Foundation of China(81700100,31771630,81572766,81702784,and 81802974);Guangdong Innovative and Entrepreneurial Research Team Program(2016ZT06S029);Natural Science Foundation of Guangdong Provinee(2017A030312009 and 2016A030313238);Special Funds for Dapeng New District Industry Development(KY20160309).

摘　　要：Bromodomain-containing proteins are known readers of histone acetylation that regulate chromatin structure and transcription.Although the functions of bromodomain-containing proteins in development,homeostasis,and disease states have been well studied,their role in self-renewal of hematopoietic stem and progenitor cells(HSPCs)remains poorly understood.Here,we performed a chemical screen using nine bromodomain inhibitors and found that the bromodomain and PHD finger-containing protein 1(Brpf1)inhibitor OF-1 enhanced the expansion of Lin−Sca-1+c-Kit+HSPCs ex vivo without skewing their lineage differentiation potential.Importantly,our results also revealed distinct functions of Brpf1 isoforms in HSPCs.Brpf1b promoted the expansion of HSPCs.By contrast,Brpf1a is the most abundant isoform in adult HSPCs but enhanced HSPC quiescence and decreased the HSPC expansion.Furthermore,inhibition of Brpf1a by OF-1 promoted histone acetylation and chromatin accessibility leading to increased expression of self-renewal-related genes(e.g.Mn1).The phenotypes produced by OF-1 treatment can be rescued by suppression of Mn1 in HSPCs.Our findings demonstrate that this novel bromodomain inhibitor OF-1 can promote the clinical application of HSPCs in transplantation.

关 键 词：Brpf1 inhibitor OF-1 Brpf1a MN1 HEMATOPOIETIC stem and PROGENITOR cell EXPANSION 

分 类 号：R329.2[医药卫生—人体解剖和组织胚胎学]