Noncoding RNA, ncRNA-a3, Epigenetically Regulates TAL1 Transcriptional Program During Erythropoiesis

Hematopoietic transcription is a combinatorial control of transcription factors, chromatin modifiers, and non-coding RNAs. TAL1 is a critical regulator of normal and malignant hematopoiesis. However, mechanism underlying regulation of TAL1 activity during erythropoiesis versus leukemogenesis remains elusive. Here, we showed that an enhancer RNA, ncRNA-a3 transcribed from TAL1 + 51Kb-enhancer, is positively correlated with TAL1 locus chromatin accessibility and transcription, and required for TAL1 activation during EPO-induced erythropoiesis. Loss of ncRNA-a3 in CD34⁺ hematopoietic stem and progenitor cells leads to reduction of TAL1 transcription, followed by impaired terminal erythroid differentiation. The effect of ncRNA-a3 loss on erythroid differentiation is partially rescued by overexpression of Tal1 cDNA, suggesting an important role of ncRNA-a3/TAL1 regulatory axis in erythropoiesis. Mechanistically, ncRNA-a3 regulates long-range chromatin interactions between +51Kb erythroid-specific enhancer, promoter and other regulatory elements in the TAL1 locus to maintain the erythroid interaction hub. By facilitating the binding and recruitment of p300/BRG1 to the TAL1 locus, ncRNA-a3 promotes chromatin accessibility in the TAL1 locus and activates TAL1 transcription program, including subsequent epigenetic and transcriptional activation of erythroid-specific TAL1 target genes. Our study reveals a novel role for ncRNA-a3 in TAL1 dependent erythropoiesis and establishes a new mode of ncRNA-a3 action in TAL1 transcriptional activation.