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 dis...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.展开更多
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)+2 种基金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).
文摘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.
