The super-enhancer derived alncRNA-EC7/Bloodlinc potentiates red blood cell development in trans (RNA-seq)

Enhancer-derived RNAs are thought to contribute locally to their parent enhancers’ functions. Whether large domains of clustered enhancers (super-enhancers, SEs) also produce cis-acting RNAs, however, remains unclear. Unlike typical enhancers, SEs form large spans of robustly transcribed chromatin, amassing capped and polyadenylated RNAs that are sufficiently abundant to sustain trans functions. Here, we show that one such RNA, alncRNA-EC7/Bloodlinc, is transcribed from a SE of the erythroid membrane transporter SLC4A1/BAND3 but diffuses beyond this site. Bloodlinc localizes to trans-chromosomal loci encoding critical regulators/effectors of terminal erythropoiesis and directly binds chromatin-organizing and transcription factors, including the chromatin attachment factor HNRNPU. Inhibiting Bloodlinc or Hnrnpu compromises the terminal erythropoiesis gene program, blocking red cell production, whereas expressing Bloodlinc ectopically stimulates this program and can promote erythroblast proliferation and enucleation in the absence of differentiation stimuli. Thus, Bloodlinc represents a novel type of trans-acting SE RNA that potentiates red blood cell development. RNA-seq of erythroid progenitors purified from E14.5 mouse fetal livers, transduced with shRNAs or overexpression vectors, and collected after 24 hours of ex vivo differentiation, generated by deep sequencing using the Illumina HiSeq2000 platform.