Cooperation between DNA, RNA and protein regulates gene expression and controls differentiation through interactions that connect regions of nucleic acids and protein domains and through the assembly of biomolecular condensates. Here, we report that endoderm differentiation is regulated by the interaction between the long non-coding RNA (lncRNA) DIGIT and the bromodomain and extraterminal domain protein BRD3. BRD3 forms phase-separated condensates of which the formation is promoted by DIGIT, occupies enhancers of endoderm transcription factors and is required for endoderm differentiation. BRD3 binds to histone H3 acetylated at lysine 18 (H3K18ac) in vitro and co-occupies the genome with H3K18ac. DIGIT is also enriched in regions of H3K18ac, and the depletion of DIGIT results in decreased recruitment of BRD3 to these regions. Our findings show that cooperation between DIGIT and BRD3 at regions of H3K18ac regulates the transcription factors that drive endoderm differentiation and suggest that protein–lncRNA phase-separated condensates have a broader role as regulators of transcription.

DNA、RNA 和蛋白质之间的合作通过连接核酸区域和蛋白质结构域的相互作用以及通过生物分子凝聚物的组装来调节基因表达并控制分化。在这里，我们报道内胚层分化是通过长非编码RNA（lncRNA）DIGIT与溴结构域和末端外结构域蛋白BRD3之间的相互作用来调节的。 BRD3形成相分离的凝聚物，其形成由DIGIT促进，占据内胚层转录因子的增强子并且是内胚层分化所必需的。 BRD3 在体外与 18 位赖氨酸乙酰化的组蛋白 H3 (H3K18ac) 结合，并与 H3K18ac 共同占据基因组。 DIGIT 在 H3K18ac 区域也富集，DIGIT 的耗尽导致 BRD3 向这些区域的招募减少。我们的研究结果表明，H3K18ac 区域的 DIGIT 和 BRD3 之间的合作调节驱动内胚层分化的转录因子，并表明蛋白质-lncRNA 相分离缩合物作为转录调节剂具有更广泛的作用。