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A PTIP-PA1 subcomplex promotes transcription for IgH class-switching independently from the associated MLL3/MLL4 methyltransferase complex

ABSTRACT: Class-switch recombination (CSR) diversifies antibodies for productive immune responses while maintaining stability of the B cell genome. Transcription at the immunoglobulin heavy-chain (Igh) locus targets CSRassociated DNA damage and is promoted by the BRCT domain-containing PTIP protein. Although PTIP is a unique component of the MLL3/MLL4 chromatin-modifying complex, the mechanisms for how PTIP promotes transcription remain unclear. Here we dissect the minimal structural requirements of PTIP and its different protein complexes using quantitative proteomics in primary lymphocytes. We find that PTIP functions in transcription and CSR separately from its association with the MLL3/MLL4 complex and from its localization to sites of DNA damage. We identify a tandem BRCT domain of PTIP that is sufficient for CSR and identify PA1 as its main functional protein partner. Collectively, we provide genetic and biochemical evidence that a PTIP-PA1 subcomplex functions independently from the MLL3/MLL4 complex to mediate transcription during CSR. These results further our understanding of how multi-functional chromatin-modifying complexes are organized by subcomplexes that harbor unique and distinct activities.

ORGANISM(S): Mus musculus

PROVIDER: GSE75930 | GEO | 2015/12/12

SECONDARY ACCESSION(S): PRJNA305731

REPOSITORIES: GEO

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A PTIP-PA1 subcomplex promotes transcription for IgH class-switching independently from the associated MLL3/MLL4 methyltransferase complex

Project description:Class-switch recombination (CSR) diversifies antibodies for productive immune responses while maintaining stability of the B cell genome. Transcription at the immunoglobulin heavy-chain (Igh) locus targets CSRassociated DNA damage and is promoted by the BRCT domain-containing PTIP protein. Although PTIP is a unique component of the MLL3/MLL4 chromatin-modifying complex, the mechanisms for how PTIP promotes transcription remain unclear. Here we dissect the minimal structural requirements of PTIP and its different protein complexes using quantitative proteomics in primary lymphocytes. We find that PTIP functions in transcription and CSR separately from its association with the MLL3/MLL4 complex and from its localization to sites of DNA damage. We identify a tandem BRCT domain of PTIP that is sufficient for CSR and identify PA1 as its main functional protein partner. Collectively, we provide genetic and biochemical evidence that a PTIP-PA1 subcomplex functions independently from the MLL3/MLL4 complex to mediate transcription during CSR. These results further our understanding of how multi-functional chromatin-modifying complexes are organized by subcomplexes that harbor unique and distinct activities. Genome-wide analysis of histone modifications in PA1-WT and -KO mouse activated B cells

2015-12-12 | E-GEOD-75930 | biostudies-arrayexpress

PTIP promotes chromatin changes critical for immunoglobulin class switch recombination

Project description: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 show that activated B cells deficient in the PTIP component of the MLL3 (mixed-lineage leukemia 3) /MLL4 complex display impaired histone methylation (H3K4me3) and transcription initiation of downstream switch regions at the immunoglobulin heavy-chain (Igh) locus leading to defective immunoglobulin class-switching. We also show that PTIP accumulation at DSBs contributes to class-switch recombination (CSR) and genome stability independently from 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 non-redundant role for the MLL3/MLL4 complex in altering antibody effector function. Genome-wide analysis of histone modifications, PTIP, and Pol II in PTIP-WT and PTIP-KO mouse activated B cells.

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PTIP promotes chromatin changes critical for immunoglobulin class switch recombination

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PA1-regulated genes in mouse embryonic fibroblast

Project description:PA1 has been identified as a component of a MLL3/4-containing histone methyltransferase complex. PA1 directly interacts with PTIP but not with other complex components. Since biological functions of PA1 are unknown, we used microarrays to determine which genes are regulated by PA1. To identify PA1-regulated genes, immortalized PA1 conditional knockout PA1loxP/loxP MEFs were infected with retroviruses expressing either Cre recombinase or vector alone. We prepared duplicated RNAs from either vector or Cre infected cells (PA1+/+ or PA1-/-) for 4 affymetrix microarrays.

2013-12-31 | E-GEOD-20157 | biostudies-arrayexpress

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Project description:A PTIP-PA1 subcomplex promotes transcription for IgH class-switching independently from the associated MLL3/MLL4 methyltransferase complex

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Comparison of gene expression between wild-type and PTIP deficient chicken DT40 B cells

2009-10-28 | GSE18778 | GEO

Comparison of gene expression between wild-type and PTIP deficient chicken DT40 B cells

Project description:PTIP (Pax2 transactivation domain-interacting protein) is a nuclear protein containing six BRCT domains. It has been shown that PTIP affects gene expression by controlling the activity of the transcription factor Pax2 and histone H3 lysine 4 methyltransferase complexes. In addition to its role in transcriptional regulation, PTIP has been implicated in DNA damage response. To ask if the depletion of PTIP affects the expression level of genes encoding DNA damage response factors , we compared the whole transcripts between wild-type and PTIP deficient chicken DT40 B cell lines. The total RNAs were isolated from wild-type and PTIP deficient cells (PTIP-/-/-) using Sepasol®-RNA I (Nacalai tesque, Japan). The gene expression profiles were examined using Genechip® Chicken Genome Array (Affymetrix Cat #900590), by GeneticLab co. Ltd. Japan, following Genechip® protocol.

2009-10-27 | E-GEOD-18778 | biostudies-arrayexpress

The MLL3/MLL4 branch of the COMPASS family regulates H3K4 monomethylation at enhancers

Project description:Histone H3 lysine 4 (H3K4) can be mono-, di-, and trimethylated by members of the COMPASS (COMplex of Proteins ASsociated with Set1) family from yeast to human and these modifications can be found at distinct regions of the genome. Monomethylation of histone H3K4 (H3K4me1) is relatively more enriched at metazoan enhancer regions compared to trimethylated histone H3K4 (H3K4me3), which are found at transcription start sites in all eukaryotes. Our recent studies in Drosophila demonstrated that the Trithorax-related (Trr) branch of the COMPASS family regulates enhancer activity and is responsible for the implementation of H3K4me1 at these regions. There are six COMPASS family members in mammals, two of which, MLL3 and MLL4, are most closely related to Drosophila Trr. Here, we use ChIP-seq of this class of COMPASS family members in both human HCT116 cells and mouse embryonic stem cells and find that MLL4 is preferentially found at enhancer regions. MLL3 and MLL4 are frequently mutated in cancer, and indeed, the widely used HCT116 cancer cell line contains inactivating mutations in the MLL3 gene. Using HCT116 cells in which MLL4 has also been knocked out, we demonstrate that MLL4 is a major regulator of H3K4me1 in these cells, with the greatest loss of monomethylation at enhancer regions. Moreover, we found a redundant role between Mll3 and Mll4 in enhancer H3K4 monomethylation in mouse embryonic fibroblast (MEF) cells. These findings suggest that mammalian MLL3/MLL4 function in the regulation of enhancer activity and enhancer-promoter communication during gene expression and that mutations of MLL3 and MLL4 found in cancer could exert their properties through enhancer malfunction. ChIP-Seq in mouse embryonic stem (mES) cells for MLL4. ChIP-seq of MLL4 and p300 in human parental HCT116 cells. ChIP-seq of H3K4me1, H3K4me2 and H3K4me3 in parental HCT116 cells and HCT116 cells with Mll4∆set.

2013-09-30 | E-GEOD-51176 | biostudies-arrayexpress

The MLL3/MLL4 branch of the COMPASS family regulates H3K4 monomethylation at enhancers

2013-09-30 | GSE51176 | GEO