Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B152TT, UK.
Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands.
Cell Rep. 2019 Sep 17;28(12):3022-3031.e7. doi: 10.1016/j.celrep.2019.08.040.
Acute myeloid leukemia (AML) is associated with mutations in transcriptional and epigenetic regulator genes impairing myeloid differentiation. The t(8;21)(q22;q22) translocation generates the RUNX1-ETO fusion protein, which interferes with the hematopoietic master regulator RUNX1. We previously showed that the maintenance of t(8;21) AML is dependent on RUNX1-ETO expression. Its depletion causes extensive changes in transcription factor binding, as well as gene expression, and initiates myeloid differentiation. However, how these processes are connected within a gene regulatory network is unclear. To address this question, we performed Promoter-Capture Hi-C assays, with or without RUNX1-ETO depletion and assigned interacting cis-regulatory elements to their respective genes. To construct a RUNX1-ETO-dependent gene regulatory network maintaining AML, we integrated cis-regulatory element interactions with gene expression and transcription factor binding data. This analysis shows that RUNX1-ETO participates in cis-regulatory element interactions. However, differential interactions following RUNX1-ETO depletion are driven by alterations in the binding of RUNX1-ETO-regulated transcription factors.
急性髓细胞白血病（AML）与转录和表观遗传调节基因的突变有关，这些突变会损害髓系分化。t(8;21)(q22;q22)易位产生 RUNX1-ETO 融合蛋白，该蛋白干扰造血主调控因子 RUNX1。我们之前表明，t(8;21)AML 的维持依赖于 RUNX1-ETO 的表达。其耗竭会导致转录因子结合以及基因表达的广泛变化，并启动髓系分化。然而，这些过程在基因调控网络中是如何联系的尚不清楚。为了解决这个问题，我们进行了启动子捕获 Hi-C 分析，有或没有 RUNX1-ETO 的耗竭，并将相互作用的顺式调节元件分配给它们各自的基因。为了构建维持 AML 的 RUNX1-ETO 依赖性基因调控网络，我们将顺式调节元件相互作用与基因表达和转录因子结合数据进行了整合。该分析表明，RUNX1-ETO 参与顺式调节元件的相互作用。然而，RUNX1-ETO 耗竭后差异相互作用是由 RUNX1-ETO 调节的转录因子结合的改变驱动的。
