Abstract
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.
Highlights
Hematopoietic stem cells (HSCs) are the most extensively studied stem cells with proven clinical utility (Li and Clevers, 2010)
We demonstrate that the bromodomain and PHD finger-containing protein 1 (Brpf1) inhibitor OF-1 increases the number and proportion of functional hematopoietic stem and progenitor cells (HSPCs) (Lin−Sca-1+c-Kit+ cells, LSKs) by modulating histone acetylation and chromatin accessibility of HSC self-renewal-related genes, such as Meningioma 1 (Mn1)
Three rounds of screening revealed that OF-1, a compound identified as a Brpf1 inhibitor, significantly increased LSK proportion (Figure 1D–F), and may improve HSPC expansion ex vivo
Summary
Hematopoietic stem cells (HSCs) are the most extensively studied stem cells with proven clinical utility (Li and Clevers, 2010). HSC transplantation has the potential to treat various diseases, including immunodeficiency, hematological malignancies, and other types of cancer (Copelan, 2006; Mantel et al, 2015). The lack of HLA-matched donors presents a serious limitation to allogeneic HSC transplantation. While umbilical cord blood (UCB) may one day become an alternative source of HSCs, the number of HSCs in UCB is often too low for successful transplantation (Czechowicz et al, 2007). Ex vivo hematopoietic stem and progenitor cell (HSPC) expansion would greatly improve clinical availability of transplantation therapies (Fares et al, 2014). The regulation of HSC self-renewal remains a fundamental question related to ex vivo HSPC expansion. Previous studies have identified multiple key intrinsic factors in regulation of HSC self-renewal, including chromatin-associated factors
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