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

• DOI: 10.1038/ni.2136
• Publication Date: 2011-10-30T19:40:36Z
• Authors: Malay Mandal; Sarah E Powers; Mark Maienschein-...; Elizabeth T Bartom; Keith M Hamel; Barbara L Kee; Aaron R Dinner; Marcus R Clark
• Keywords: Mice, Knockout; Mice, Inbred BALB C; 0303 health sciences; Binding Sites; Base Sequence; Gene Expression Profiling; Immunoglobulins; Histone-Lysine N-Methyltransferase; Binding, Competitive; Methylation; Epigenesis, Genetic; Histones; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Gene Expression Regulation; COS Cells; Chlorocebus aethiops; Basic Helix-Loop-Helix Transcription Factors; Animals; Cluster Analysis; Enhancer of Zeste Homolog 2 Protein

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.