ZBTB48 is a pioneer factor regulating B-cell-specific CIITA expression

CIITA is the master regulator of MHC II genes expression and hence the adaptive immune response. CIITA expression itself is tightly regulated by three cell type-specific promoters, pI, pIII, and by pIV, and can also be induced by IFNg in non-immune cells. While key regulatory elements have been identified within these promoters, knowledge of transcription factors regulating CIITA is incomplete. Here, we demonstrate that the telomere-binding protein and transcriptional activator ZBTB48 directly binds to both critical activating elements within CIITA pIII and is essential for its gene expression. ZBTB48 establishes open chromatin at CIITA pIII upstream of activating H3K4me3 modifications both priming CIITA transcription for IFNg-induction and ensuring constitutive expression in primary murine B cells. Hence, ZBTB48 acts as a molecular on-off-switch for B-cell-specific CIITA expression.