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.

中文翻译：

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Brpf1 在成体造血干细胞和祖细胞扩增中的同种型特异性参与。

含溴结构域的蛋白质是已知的组蛋白乙酰化阅读器，可调节染色质结构和转录。尽管含溴结构域蛋白在发育、稳态和疾病状态中的功能已得到充分研究，但它们在造血干细胞和祖细胞 (HSPC) 自我更新中的作用仍知之甚少。在这里，我们使用九种溴结构域抑制剂进行了化学筛选，发现溴结构域和含 PHD 指的蛋白 1 (Brpf1) 抑制剂 OF-1 增强了 Lin ⁻ Sca-1 ⁺ c-Kit ⁺ HSPCs离体的扩增不会扭曲他们的谱系分化潜力。重要的是，我们的结果还揭示了 Brpf1 异构体在 HSPC 中的不同功能。Brpf1b 促进了 HSPC 的扩增。相比之下，Brpf1a 是成人 HSPC 中最丰富的同种型，但增强了 HSPC 静止并降低了 HSPC 扩增。此外，OF-1 对 Brpf1a 的抑制促进了组蛋白乙酰化和染色质可及性，从而导致自我更新相关基因（例如Mn1）的表达增加。OF-1 处理产生的表型可以通过抑制 HSPC 中的 Mn1 来挽救。我们的研究结果表明，这种新型溴结构域抑制剂 OF-1 可以促进 HSPCs 在移植中的临床应用。