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

Malay Mandal, Sarah E. Powers, Mark Maienschein-Cline, Elizabeth T. Bartom, Keith M. Hamel, Barbara L. Kee, Aaron R. Dinner, Marcus R. Clark*

*Corresponding author for this work

Research output: Contribution to journalArticle

113 Scopus citations

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 (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.

Original languageEnglish (US)
Pages (from-to)1212-1220
Number of pages9
JournalNature Immunology
Volume12
Issue number12
DOIs
StatePublished - Dec 1 2011

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Mandal, M., Powers, S. E., Maienschein-Cline, M., Bartom, E. T., Hamel, K. M., Kee, B. L., Dinner, A. R., & Clark, M. R. (2011). Epigenetic repression of the Igk locus by STAT5-mediated recruitment of the histone methyltransferase Ezh2. Nature Immunology, 12(12), 1212-1220. https://doi.org/10.1038/ni.2136