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

M Mandal, SE Powers, M Maienschein-Cline… - Nature …, 2011 - nature.com
M Mandal, SE Powers, M Maienschein-Cline, ET Bartom, KM Hamel, BL Kee, AR Dinner
Nature immunology, 2011nature.com
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 (Eκi), which led to recruitment of the histone …
Abstract
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 (Eκi), which led to recruitment of the histone methyltransferase Ezh2. Ezh2 marked trimethylation of histone H3 at Lys27 (H3K27me3) throughout the κ-chain joining region (Jκ) to the κ-chain constant region (Cκ). 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 Eκi, 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.
nature.com