JMJD1C facilitates long distance genomic interactions by promoting condensates formation of key leukemic transcription factors in multiple AML cells [RNA-seq]
Dysregulation of transcriptional programs that establish and maintain specific cell identities can lead to various diseases, especially cancer. Acute myeloid leukemia (AML) is an extremely heterogeneous malignancy with frequent genetic mutations such as transcription factors (TFs) and epigenetic factors, resulting in gene dysregulation, differentiation blockade and aberrant proliferation of immature clonal myeloid cells. Various AML subtypes usually involve in distinct genetic alterations, and most studies and therapeutic drugs are focused on specific AML genetic abnormalities. However, whether these seemingly different AML subtypes share a universal transcriptional programs and regulation mechanism is not clear. Identification of such program could help finding of common vulnerabilities and thus future therapeutics against multiple AML subtypes. In this study, we set out to elucidate the underlying mechanism that explains the general dependency towards JMJD1C by AML with different genetic backgrounds. Towards this goal, we first identify RUNX1 as a transcription factor that recruits JMJD1C to chromatin in multiple types of leukemia. Second, we show that JMJD1C directly interacts with RUNX1 at the N-terminus and they co-regulate a set of genes required by leukemic cells. Finally, we found that the N-terminus of JMJD1C could form liquid-like biomolecular RUNX1-containing condensates that are independent of its enzymatic activity, to mediate promoter-enhancer interactions to activate downstream gene expression. Overall design: RNA-seq when RUNX1 was knocked-down in Kasumi-1 and MOLM13 cells and RNA-seq when JMJD1C was knocked-down in MOLM13 cells.