PTIP Promotes Chromatin Changes Critical for Immunoglobulin Class Switch Recombination

Abstract

Programmed genetic rearrangements in lymphocytes require transcription at antigen receptor genes to promote accessibility for initiating double-strand break (DSB) formation critical for DNA recombination and repair. Here, we showed that activated B cells deficient in the PTIP component of the MLL3 (mixed-lineage leukemia 3)-MLL4 complex display impaired trimethylation of histone 3 at lysine 4 (H3K4me3) and transcription initiation of downstream switch regions at the immunoglobulin heavy-chain (Igh) locus, leading to defective immunoglobulin class switching. We also showed that PTIP accumulation at DSBs contributes to class switch recombination (CSR) and genome stability independently of Igh switch transcription. These results demonstrate that PTIP promotes specific chromatin changes that control the accessibility of the Igh locus to CSR and suggest a nonredundant role for the MLL3-MLL4 complex in altering antibody effector function.

A phosphorylation switch on RbBP5 regulates histone H3 Lys4 methylation

“…These observations are also consistent with recent studies showing that deletion of MLL3 in NIH3T3-L1 cells results in a significant loss of H3K4me3 at the promoter region of the adipogenic marker gene aP2 . Moreover, B-cell-specific knockout of PTIP, a subunit associating with MLL3/MLL4 complexes (Cho et al 2007;Issaeva et al 2007), results in a loss of H3K4me3 at specific Igh switch regions upon LPS stimulation (Daniel et al 2010). These seemingly contrasting results potentially point to a model in which RbBP5 phosphorylation can act as a switch increasing MLL3 kinetics, facilitating the formation of H3K4me1 that can potentially be further methylated to ultimately form H3K4me2/3.…”

Uniform, optimal signal processing of mapped deep-sequencing data

“…11) and two poorly characterized loci associated with neurodevelopmental disorders 34,35 . Having qualitatively validated forebrain HPT, we used EFilter to predict mRNA levels in seven additional cell types (NPC, embryonic stem (ES) cell, mouse embryonic fibroblast, B-cell, myoblast, myotube and 3T3-L1 pre-adipocyte), based on H3K4me3 and H3K36me3 ChIP-seq data from previous studies 31,33,36,37 . Sample-specific gene expression was estimated as the log-ratio relative to the median of the eight samples.…”

The Groucho-associated Phosphatase PPM1B Displaces Pax Transactivation Domain Interacting Protein (PTIP) to Switch the Transcription Factor Pax2 from a Transcriptional Activator to a Repressor

“…PTIP is required for maintaining high levels of H3K4me3 in ES cells (33) and in early embryonic development (10). PTIP-mediated H3K4me3 is observed at the germ line transcript promoters of the heavy-chain Ig locus upon activation of B cells to undergo class switch recombination (34), where it promotes Pax5-dependent changes in transcription and chromatin looping (30). PTIP is also needed in adult cardiomyocytes (35) to maintain the normal pattern of gene expression and in glomerular podocytes (36).…”