A lncRNA identifies <i>Irf8</i> enhancer element in negative feedback control of dendritic cell differentiation.

Abstract

Transcription factors play a determining role in lineage commitment and cell differentiation. Interferon regulatory factor 8 (IRF8) is a lineage determining transcription factor in hematopoiesis and master regulator of dendritic cells (DC), an important immune cell for immunity and tolerance. IRF8 is prominently upregulated in DC development by autoactivation and controls both DC differentiation and function. However, it is unclear how <i>Irf8</i> autoactivation is controlled and eventually limited. Here, we identified a novel long non-coding RNA transcribed from the +32 kb enhancer downstream of <i>Irf8</i> transcription start site and expressed specifically in mouse plasmacytoid DC (pDC), referred to as <i>lncIrf8</i>. The <i>lncIrf8</i> locus interacts with the <i>lrf8</i> promoter and shows differential epigenetic signatures in pDC versus classical DC type 1 (cDC1). Interestingly, a sequence element of the <i>lncIrf8</i> promoter, but not <i>lncIrf8</i> itself, is crucial for mouse pDC and cDC1 differentiation, and this sequence element confers feedback inhibition of <i>Irf8</i> expression. Taken together, in DC development <i>Irf8</i> autoactivation is first initiated by flanking enhancers and then second controlled by feedback inhibition through the <i>lncIrf8</i> promoter element in the +32 kb enhancer. Our work reveals a previously unrecognized negative feedback loop of <i>Irf8</i> that orchestrates its own expression and thereby controls DC differentiation.