Epigenetic repression of the Igk locus by STAT5-mediated recruitment of the histone methyltransferase Ezh2

The transcription factor STAT5 commonly activates gene transcription. Clark and colleagues show that tetrameric STAT5, induced by high concentrations of interleukin 7, can repress gene expression by recruitment of the histone methyltransferase Ezh2. During B lymphopoiesis, recombination of the locus encoding the immunoglobulin κ-chain complex ( Igk ) requires expression of the precursor to the B cell antigen receptor (pre-BCR) and escape from signaling via the interleukin 7 receptor (IL-7R). By activating the transcription factor STAT5, IL-7R signaling maintains proliferation and represses Igk germline transcription by unknown mechanisms. We demonstrate that a STAT5 tetramer bound the Igk intronic enhancer (E κi ), which led to recruitment of the histone methyltransferase Ezh2. Ezh2 marked trimethylation of histone H3 at Lys27 (H3K27me3) throughout the κ-chain joining region (J κ ) to the κ-chain constant region (C κ ). In the absence of Ezh2, IL-7 failed to repress Igk germline transcription. H3K27me3 modifications were lost after termination of IL-7R–STAT5 signaling, and the transcription factor E2A bound E κi , which resulted in acquisition of H3K4me1 and acetylated histone H4 (H4Ac). Genome-wide analyses showed a STAT5 tetrameric binding motif associated with transcriptional repression. Our data demonstrate how IL-7R signaling represses Igk germline transcription and provide a general model for STAT5-mediated epigenetic transcriptional repression.