PTIP Promotes Chromatin Changes Critical for Immunoglobulin Class Switch Recombination

Abstract

PTIP in Immunoglobulin Switching One of the hallmarks of humoral immunity is the ability of immunoglobulins (Ig) to undergo class switch recombination (CSR). Through genetic recombining of the Ig heavy chain, Igs maintain their antigen specificity but gain the ability to interact with different cell surface receptors required for successful pathogen clearance. CSR requires transcription at the Ig heavy chain locus to initiate genetic rearrangement. Changes in chromatin accessibility are thought to promote CSR-associated transcription. Daniel et al. (p. 917 , published online 29 July; see the Perspective by Singh and Demarco ) now show that trimethylation of histone 3 at lysine 4 (H3K4me3) controls the accessibility of the Ig heavy chain locus to CSR and that PTIP (Pax interaction with transcription-activation domain protein-1), a component of the histone methylase complex, is required for this modification. Mouse PTIP-deficient B cells exhibited impaired CSR. PTIP was required both for the recruitment RNA Polymerase II and for subsequent chromatin remodeling, including histone acetylation, which occurs during CSR. Largely independent of its function in transcription initiation in CSR, PTIP also associated with double-stranded DNA breaks during CSR and promoted genome stability. These dual functions of PTIP may be important for the precise coordination of chromatin accessibility and recombination required during CSR.