Runt‐related transcription factor 1 (RUNX1) plays an important role in normal haematopoietic cell development and function, and its function is frequently disrupted in leukaemia. RUNX1 is widely recognised as a sequence‐specific DNA binding factor that recognises the motif 5′‐TG(T/C)GGT‐3′ in promoter and enhancer regions of its target genes. Moreover, RUNX1 fusion proteins, such as RUNX1‐ETO formed by the t(8;21) translocation, retain the ability to recognise and bind to this sequence to elicit atypical gene regulatory effects on bona fide RUNX1 targets. However, our analysis of publicly available RUNX1 chromatin immunoprecipitation sequencing (ChIP‐Seq) data has provided evidence challenging this dogma, revealing that this motif‐specific model of RUNX1 recruitment and function is incomplete. Our analyses revealed that the majority of RUNX1 genomic localisation occurs outside of promoters, that 20% of RUNX1 binding sites lack consensus RUNX motifs, and that binding in the absence of a cognate binding site is more common in promoter regions compared to distal sites. Reporter assays demonstrate that RUNX1 can drive promoter activity in the absence of a recognised DNA binding motif, in contrast to RUNX1‐ETO. RUNX1‐ETO supresses activity when it is recruited to promoters containing a sequence specific motif, while interestingly, it binds but does not repress promoters devoid of a RUNX1 recognition site. These data suggest that RUNX1 regulation of target genes occurs through multiple mechanisms depending on genomic location, the type of regulatory element and mode of recruitment.

中文翻译：

---

RUNX1 在没有同源 DNA 结合基序的情况下调节启动子活性

Runt 相关转录因子 1 (RUNX1) 在正常造血细胞发育和功能中发挥着重要作用，其功能在白血病中经常被破坏。 RUNX1 被广泛认为是一种序列特异性 DNA 结合因子，可识别其靶基因启动子和增强子区域中的基序 5'-TG(T/C)GGT-3'。此外，RUNX1融合蛋白，例如由t(8;21) 易位，保留识别和结合该序列的能力，以对真正的 RUNX1 靶标产生非典型基因调控作用。然而，我们对公开的 RUNX1 染色质免疫沉淀测序 (ChIP-Seq) 数据的分析提供了挑战这一教条的证据，表明这种 RUNX1 招募和功能的基序特异性模型是不完整的。我们的分析表明，大多数 RUNX1 基因组定位发生在启动子之外，20% 的 RUNX1 结合位点缺乏共有的 RUNX 基序，并且与远端位点相比，在缺乏同源结合位点的情况下的结合在启动子区域中更为常见。报告基因检测表明，与 RUNX1-ETO 相比，RUNX1 在缺乏公认的 DNA 结合基序的情况下可以驱动启动子活性。当 RUNX1-ETO 被招募到含有序列特异性基序的启动子时，它会抑制活性，而有趣的是，它会结合但不抑制缺乏 RUNX1 识别位点的启动子。这些数据表明，RUNX1 对靶基因的调节通过多种机制发生，具体取决于基因组位置、调节元件的类型和招募模式。