A lncRNA identifies IRF8 enhancer element in negative feedback control of dendritic cell differentiation

Transcription factors play a determining role in lineage commitment and cell differentiation. Interferon regulatory factor 8 (IRF8), a hematopoietic transcription factor, is prominently upregulated in dendritic cells (DC) by autoactivation and controls DC differentiation and function. However, it is unclear how IRF8 autoactivation is controlled and eventually limited. Here we identified a novel long non-coding RNA transcribed from the +32 kb enhancer downstream of IRF8 transcription start site and expressed specifically in plasmacytoid DC (pDC), referred to as lncIRF8. A sequence element of the lncIRF8 promoter, but not lncIRF8 itself, is crucial for pDC and classical DC type 1 (cDC1) differentiation. In DC development IRF8 autoactivation is first initiated by flanking enhancers and then second controlled by feedback inhibition through the lncIRF8 promoter element in the +32 kb enhancer. Our work reveals a previously unrecognized negative feedback loop of IRF8 that orchestrates its own expression and thereby controls DC differentiation.