Epigenetic repression of the Igk locus by STAT5-mediated 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.
Department of Medicine, Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, Illinois, USA.
Malay
M
Mandal
Sarah E
SE
Powers
Mark
M
Maienschein-Cline
Elizabeth T
ET
Bartom
Keith M
KM
Hamel
Barbara L
BL
Kee
Aaron R
AR
Dinner
Marcus R
MR
Clark
D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D001667:Binding, Competitive; D019556:COS Cells; D002522:Chlorocebus aethiops; D016000:Cluster Analysis; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D007136:Immunoglobulins / Q000235:genetics*; D008745:Methylation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063151:Polycomb Repressive Complex 2; D011485:Protein Binding; D020395:Receptors, Interleukin-7 / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
D051792:Basic Helix-Loop-Helix Proteins; D000071221:Enhancer of Zeste Homolog 2 Protein; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D007136:Immunoglobulins; D063151:Polycomb Repressive Complex 2; D020395:Receptors, Interleukin-7; D050799:STAT5 Transcription Factor; C014609:IgK; C075668:Tcf3 protein, mouse; C498410:Ezh2 protein, mouse