lncRNA and protein team up to drive immune cell identity

In this issue ofBlood, Waliullah et al 1 identified a novel feed-forward loop (FFL) that is induced by transcription factor (TF) CCAAT enhancer-binding protein (C/EBP).This FFL is composed of TF PU.1 (SPI1) and the long noncoding RNA (lncRNA) LOUP (also known as SLC39A13-AS1), which drives monocyte/macrophage (Mo/M) differentiation and innate immune function (see figure).The gene encoding LOUP is located ~17 kb upstream of the PU.1 promoter and originates from the PU.1 upstream regulatory element (URE).LOUP encodes a 1-directional enhancer RNA (eRNA) of ~2.7 kb that induces PU.1 expression by mediating URE promoter chromatin looping. 2 Recent work by Halasz et al 3 did identify LOUP as a regulator of PU.1; however, the molecular mechanism that underlies this regulation has not been elucidated previously.