YY1 controls Igκ repertoire and B cell development, and localizes with condensin on the Igκ locus

Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
The EMBO Journal (Impact Factor: 10.43). 03/2013; 32(8). DOI: 10.1038/emboj.2013.66
Source: PubMed


Conditional knock-out (KO) of Polycomb Group (PcG) protein YY1 results in pro-B cell arrest and reduced immunoglobulin locus contraction needed for distal variable gene rearrangement. The mechanisms that control these crucial functions are unknown. We deleted the 25 amino-acid YY1 REPO domain necessary for YY1 PcG function, and used this mutant (YY1ΔREPO), to transduce bone marrow from YY1 conditional KO mice. While wild-type YY1 rescued B-cell development, YY1ΔREPO failed to rescue the B-cell lineage yielding reduced numbers of B lineage cells. Although the IgH rearrangement pattern was normal, there was a selective impact at the Igκ locus that showed a dramatic skewing of the expressed Igκ repertoire. We found that the REPO domain interacts with proteins from the condensin and cohesin complexes, and that YY1, EZH2 and condensin proteins co-localize at numerous sites across the Ig kappa locus. Knock-down of a condensin subunit protein or YY1 reduced rearrangement of Igκ Vκ genes suggesting a direct role for YY1-condensin complexes in Igκ locus structure and rearrangement.

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Available from: Junwen Wang, Oct 03, 2015
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    • "As predicted, we identified clusters of YY1 binding sites across the Igκ locus that binds to YY1 (85). We found that PcG protein EZH2 co-localized with YY1 at these sites apparently as a result of recruitment by YY1 (85). We also identified several proteins that physically interact with the YY1 REPO domain providing potential insight into the mechanism of YY1 function in locus contraction. "
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    ABSTRACT: During B cell development, long-distance DNA interactions are needed for V(D)J somatic rearrangement of the immunoglobulin (Ig) loci to produce functional Ig genes, and for class switch recombination (CSR) needed for antibody maturation. The tissue-specificity and developmental timing of these mechanisms is a subject of active investigation. A small number of factors are implicated in controlling Ig locus long-distance interactions including Pax5, Yin Yang 1 (YY1), EZH2, IKAROS, CTCF, cohesin, and condensin proteins. Here we will focus on the role of YY1 in controlling these mechanisms. YY1 is a multifunctional transcription factor involved in transcriptional activation and repression, X chromosome inactivation, Polycomb Group (PcG) protein DNA recruitment, and recruitment of proteins required for epigenetic modifications (acetylation, deacetylation, methylation, ubiquitination, sumoylation, etc.). YY1 conditional knock-out indicated that YY1 is required for B cell development, at least in part, by controlling long-distance DNA interactions at the immunoglobulin heavy chain and Igκ loci. Our recent data show that YY1 is also required for CSR. The mechanisms implicated in YY1 control of long-distance DNA interactions include controlling non-coding antisense RNA transcripts, recruitment of PcG proteins to DNA, and interaction with complexes involved in long-distance DNA interactions including the cohesin and condensin complexes. Though common rearrangement mechanisms operate at all Ig loci, their distinct temporal activation along with the ubiquitous nature of YY1 poses challenges for determining the specific mechanisms of YY1 function in these processes, and their regulation at the tissue-specific and B cell stage-specific level. The large numbers of post-translational modifications that control YY1 functions are possible candidates for regulation.
    Frontiers in Immunology 02/2014; 5:45. DOI:10.3389/fimmu.2014.00045
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    • "Either of these recruitment pathways would lead to ubiquitination of H2A on lysine 119. In addition, our published work showed that YY1 interacts with EZH2 and SUZ12 (PRC2 components) (59) thereby recruiting the PRC2 complex resulting in trimethylation of histone H3 at lysine 27. "
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    ABSTRACT: Polycomb Group (PcG) proteins are crucial for epigenetic inheritance of cell identity and are functionally conserved from Drosophila to humans. PcG proteins regulate expression of homeotic genes and are essential for axial body patterning during development. Earlier we showed that transcription factor YY1 functions as a PcG protein. YY1 also physically interacts with YAF2, a homolog of RYBP. Here we characterize the mechanism and physiologic relevance of this interaction. We found phenotypic and biochemical correction of dRYBP mutant flies by mouse YAF2 demonstrating functional conservation across species. Further biochemical analysis revealed that YAF2 bridges interaction between YY1 and the PRC1 complex. ChIP assays in HeLa cells showed that YAF2 is responsible for PcG recruitment to DNA, which is mediated by YY1 DNA binding. Knock-down of YY1 abrogated PcG recruitment, which was not compensated by exogenous YAF2 demonstrating that YY1 DNA binding is a priori necessary for Polycomb assembly on chromatin. Finally, we found that although YAF2 and RYBP regulate a similar number of Polycomb target genes, there are very few genes that are regulated by both implying functional distinction between the two proteins. We present a model of YAF2-dependent and independent PcG DNA recruitment by YY1.
    Nucleic Acids Research 11/2013; 42(4). DOI:10.1093/nar/gkt1187 · 9.11 Impact Factor
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    ABSTRACT: Despite frequent exposures to a variety of potential triggers, including antigens produced by pathogens or commensal microbiota, B-lymphocytes are able to mount highly protective responses to a variety of threats, while remaining tolerant to self-components. A number of cytokines, signaling pathways and transcription factors have been characterized to elucidate the mechanisms underlying B cell tolerance to self. It is, however, unclear how the signals received by B-lymphocytes are converted into complex and sustained patterns of gene expression that can allow production of protective antibodies and maintain immune tolerance to self-components. Mounting evidence now suggests an important role for epigenetic mechanisms in modulating and transmitting signals for B lymphocyte tolerization to self-antigens. It is likely that a better insight into epigenetic regulation of B cell tolerance will lead to development of gene-specific therapeutic approaches that optimize host defense mechanisms to exogenous threats, while preventing development and/or progression of autoimmune inflammatory diseases.
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