LAUSR

&NA; The cell fate decision between interferon‐producing plasmacytoid DC (pDC) and antigen‐presenting classical DC (cDC) is controlled by the E protein transcription factor TCF4 (E2‐2). We report that TCF4 comprises two transcriptional isoforms, both of which are required for optimal pDC development in vitro. The long Tcf4 isoform is expressed specifically in pDCs, and its deletion in mice impaired pDCs development and led to the expansion of non‐canonical CD8+ cDCs. The expression of Tcf4 commenced in progenitors and was further upregulated in pDCs, correlating with stage‐specific activity of multiple enhancer elements. A conserved enhancer downstream of Tcf4 was required for its upregulation during pDC differentiation, revealing a positive feedback loop. The expression of Tcf4 and the resulting pDC differentiation were selectively sensitive to the inhibition of enhancer‐binding BET protein activity. Thus, lineage‐specifying function of E proteins is facilitated by lineage‐specific isoform expression and by BET‐dependent feedback regulation through distal regulatory elements. Graphical Abstract Figure. No caption available. HighlightsTwo functional isoforms of the E protein factor TCF4 (E2‐2) are expressed in pDCsThe “long” TCF4 isoform is pDC specific and controls pDC development in vivoA conserved enhancer controls TCF4 expression and pDC developmentTCF4 expression and pDC development are sensitive to BET protein inhibitors &NA; The development of plasmacytoid dendritic cells is driven by E protein transcription factor TCF4 (E2‐2). Grajkowska et al. show that TCF4 itself is controlled by multiple mechanisms including isoform‐specific expression and positive feedback regulation through distal regulatory elements.