Noncoding RNA, <i>ncRNA-a3</i> , 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, <i>ncRNA-a3</i> transcribed from <i>TAL1 + 51</i>Kb-enhancer, is positively correlated with <i>TAL1</i> locus chromatin accessibility and transcription, and required for <i>TAL1</i> activation during EPO-induced erythropoiesis. Loss of <i>ncRNA-a3</i> in CD34⁺ hematopoietic stem and progenitor cells leads to reduction of <i>TAL1</i> transcription, followed by impaired terminal erythroid differentiation. The effect of <i>ncRNA-a3</i> loss on erythroid differentiation is partially rescued by overexpression of <i>Tal1</i> cDNA, suggesting an important role of <i>ncRNA-a3</i>/TAL1 regulatory axis in erythropoiesis. Mechanistically, <i>ncRNA-a3</i> regulates long-range chromatin interactions between <i>+51</i>Kb erythroid-specific enhancer, promoter and other regulatory elements in the <i>TAL1</i> locus to maintain the erythroid interaction hub. By facilitating the binding and recruitment of p300/BRG1 to the <i>TAL1</i> locus, <i>ncRNA-a3</i> promotes chromatin accessibility in the <i>TAL1</i> locus and activates <i>TAL1</i> transcription program, including subsequent epigenetic and transcriptional activation of erythroid-specific TAL1 target genes. Our study reveals a novel role for <i>ncRNA-a3</i> in TAL1 dependent erythropoiesis and establishes a new mode of <i>ncRNA-a3</i> action in <i>TAL1</i> transcriptional activation.