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Benjamin Bonavida - One of the best experts on this subject based on the ideXlab platform.
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abstract 4687 oncogenic role of the transcription factor YY1 and its target survivin in non hodgkin s lymphoma
Cancer Research, 2020Co-Authors: Silvia Vivarelli, Benjamin Bonavida, Luca Falzone, Saverio Candido, Massimo LibraAbstract:Objective Yin Yang 1 (YY1) is a transcription factor with a dual role in cancer genesis. Hematological malignancies, including non-Hodgkin lymphomas (NHL), are often characterized by a frequent development of resistance to therapy and a high rate of tumor recurrence. Our previous observations showed that YY1 is overexpressed in hematological tumors. The aim of this study was to investigate the functional role of YY1 in anti-cancer therapy induced cell death and to identify YY1 downstream resistant factors. Experimental Designs The NHL Raji cell line was used as a cellular model. The expression of YY1 was assessed by q-PCR and WB. YY1 knock-down (KD) was achieved using retroviral shRNA. Viability was measured by both the MTT assay and the Trypan Blue live/dead cell count. Cell death was induced following Vincristine and Doxorubicin treatments. The following analyses were used in this study: the JASPAR database, the Encyclopedia of DNA Elements (ENCODE) and the Cancer Genome Atlas (TCGA) datasets relative to NHL patients have been analyzed to assess the expression levels of YY1 and apoptotic genes, according to tumor stages and patients9 clinical-pathological features. Results Silencing of YY1 in Raji cells resulted in increased sensitivity to both Vincristine and Doxorubicin treatments and augmented apoptosis. Jaspar analysis identified several potential YY1 transcriptional targets involved in cellular death regulation. As a result of q-PCR screening and validation, Survivin has been identified as a potential YY1 target, as it was significantly downregulated following YY1 KD. Bioinformatic analysis of deposited Chip-Seq databases in ENCODE revealed that YY1 is able to target Survivin transcriptional regulatory regions in different cancer cell lines, as well as in normal B lymphocytes. The TCGA-deposited datasets identified specific clusters of YY1 expression significantly correlated with Survivin. Conclusions Our findings demonstrated that (1) YY1 silencing resulted in the sensitization of Raji tumor cells to drug-induced apoptosis (2) q-PCR-mediated screening of putative YY1 targets led to the identification of Survivin as a potential YY1 target, as when YY1 was KD, Survivin levels were strongly downregulated (3) YY1 might be positively regulating Survivin expression (4) Survivin could be a potential target of YY1 in NHL and (5) YY1 and Survivin in NHL may represent two novel diagnostic and prognostic biomarkers to assess patients9 response to chemotherapy. Citation Format: Silvia Vivarelli, Luca Falzone, Saverio Candido, Benjamin Bonavida, Massimo Libra. Oncogenic role of the transcription factor YY1 and its target Survivin in non-Hodgkin9s lymphoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4687.
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Crosstalks between Yin-Yang 1 (YY1) and autophagy in cancer
Autophagy in Immune Response: Impact on Cancer Immunotherapy, 2020Co-Authors: Benjamin BonavidaAbstract:Abstract The transcription factor Yin Yang 1 (YY1) is overexpressed in the majority of human cancers and is closely linked in the regulation of the various phenotypic properties of cancer. YY1 regulates cell viability, cell proliferation, migration, invasion, EMT, metastasis, and the resistance to chemo-immuno-therapeutic cytotoxic drugs. Its overexpression has also been associated with poor prognosis. Autophagy is a cellular process that cancer cells regulate for their own survival under stress conditions. Hence, both YY1 and autophagy share common properties in cancer and, therefore, it was hypothesized that YY1 may regulate autophagy in cancer via several crosstalk signaling pathways. The analyses identified, indeed, the presence of multiple crosstalks that primarily consisted of the followings: (1) the YY1/p53 autophagy axis, (2) the YY1/Atg genes autophagy axis, (3) the YY1/LC3 autophagy axis, (4) the YY1/miR 30a autophagy axis, (5) the YY1/miR 372 autophagy axis, and (6) the dysregulated NF-kB/SNAIL/YY1/RKIP/PTEN autophagy axis. Clearly, these various crosstalks supported the proposed hypothesis and demonstrated an additional activity for YY1 in the regulation of autophagy in cancer. The implication of these findings is that targeting either the crosstalk pathways and/or directly YY1 may be detrimental to the tumor cell survival, growth, invasion, metastasis, resistance and, subsequently, leading to tumor regression.
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involvement of yin yang 1 YY1 expression in t cell subsets differentiation and their functions implications in t cell mediated diseases
Critical Reviews in Immunology, 2019Co-Authors: Feodora Roxanne Kosasih, Benjamin BonavidaAbstract:The transcription factor Yin Yang 1 (YY1) has been implicated in embryogenesis, cell differentiation, organ development, and regulation of T cell-mediated immune diseases. YY1 has been reported to act as an activator or repressor, or both, of various genes depending on the nature of the tissue and their context. Although the roles of YY1 in both pathogenesis and progression of tumors has been the subject of many reports, the roles of YY1 in the immune system are not as well known. In this review, we examine the literature on the role of YY1 in both the differentiation and the development of various subsets of the T lymphocytes and examined its molecular role in these areas. We examined the role of YY1 in the thymus for the development of both CD4 and CD8 T lymphocytes, the various CD4 subsets, Th1, Th2, Th17, and Treg. Our analyses revealed that the presence of YY1 is necessary for maturation and proliferation of the αβ lineage through its role in mediating the apoptotic pathway. Moreover, in differentiation of T cell subsets, YY1 controls the expression of the Th2 master regulator GATA3, the Treg inducer Foxp3, as well as IL-12 expression, which is important in regulating production of Th1 cytokines. Furthermore, the role of YY1 in the Th17 signaling pathway has not been fully identified, although recent studies have suggested that differentiation of Th17 involves synergistic action of YY1 and STAT3. The previously mentioned findings strongly suggest that the role of YY1 in T cells is critical in both their normal differentiation and the induction of T cell-mediated autoimmune diseases. Clearly, such findings suggest the potential therapeutic applications of YY1 inhibitors to alleviate its role in autoimmune diseases.
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The Forgotten YY2 in Reported YY1 Expression Levels in Human Cancers.
Critical reviews in oncogenesis, 2017Co-Authors: Samantha Kaufhold, Nabil Aziz, Benjamin BonavidaAbstract:The transcription factor Yin Yang 1 (YY1) has been reported to be overexpressed in the majority of human cancers and that overexpression has prognostic significance. YY1 regulates several properties associated with cancer cells, including cell survival, cell proliferation, endothelial-mesenchymal transition, metastases, and resistance to both chemotherapeutics and immunotherapeutics. Although the majority of published reports focus on YY1 levels, little has been reported on the expression and activity of YY1 family member Yin Yang 2 (YY2). YY1 and YY2 share more than 50% homologies in DNA and amino acid sequences and share the same C-terminal zinc finger domains involved in DNA binding. This survey of the reported literature revealed that the antibodies used in published immunohistochemistry analyses were not uniquely specific for YY1. Most were likely cross-reactive with YY2. Furthermore, data from the Human Protein Atlas regarding YY1 and YY2 expression in various cancers were generated using antibodies that did not discriminate between YY1 and YY2. This review analyzed the commercially available antibodies listed against YY1 and YY2 and determined their cross-reactivities. A summary is of the published studies on the expression levels of YY1 in human cancers and their potential cross-reactivities with YY2 is also provided. Well-documented monospecific antibodies to both YY1 and YY2 have to be developed and used when examining the expression levels of YY1 and YY2 in human cancers to elucidate the accurate relationship between them and clinical significance of each.
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yin yang 1 YY1 acting primarily as an oncogene and rarely as a tumor suppressor in distinct hematological malignancies prognostic and therapeutic implications
Blood, 2016Co-Authors: Samantha Kaufhold, Massimo Libra, Hermes Garban, Stephanie Wottrich, Benjamin BonavidaAbstract:Yin Yang 1 (YY1) is a transcription factor that is ubiquitously expressed in many normal and cancerous tissues. This transcription factor was reported to have contradictory functions, consistent with its name, and it was shown to either activate and/or repress several gene products. The role of YY1 in cancer was initially reported to be overexpressed in a large number of solid cancers, and its overexpression was suggested to be of prognostic significance (Shi et al, Curr Cancer Drug Targets 2015;15:145-57). In addition, YY1 was also shown to be a pivotal factor in both drug and immune resistance, as well as it plays an important role in invasion and metastasis (Bonavida and Baritaki, Critical Reviews in Oncogenesis 2011;16:211-226). The reported protein expression and mRNA expressions derived from Oncomine datasets were examined to assess the functions of YY1 in a large number of hematological malignancies (Bonavida and Kaufhold, Pharmacol Ther 2015;150:149-68). However, YY1 expression was not reported in all cancer types. Our preliminary findings suggested that YY1 may act either as an oncogene or as a tumor suppressor in distinct types of hematological malignancies. In multiple myeloma (MM), YY1 protein overexpression was reported and shown to be complexed with the NF-κB subunit RelA. In addition, computational analysis revealed that increased YY1 transcript levels were observed in MM. These findings suggested that YY1 may act as an oncogene in MM, and the supporting data demonstrated that knockdown of YY1 resulted in cell death of MM cell lines. Further bioinformatic analyses showed that YY1 was overexpressed in AML patient-derived tumor tissues. In contrast to AML, bioinformatics analysis revealed that YY1 mRNA was not upregulated in chronic lymphocytic leukemia (CLL) and no significant differences were observed when compared to normal tissues. Clearly, these findings suggested that YY1 may be acting as an oncogene in AML but as a tumor suppressor in CLL. In B-cell non-Hodgkin lymphoma (NHL), the overexpression of YY1 at both mRNA and protein levels suggests its involvement in the malignant transformation. Overall, these data strongly support the notion of the oncogenic role played by the transcription factor YY1 in the majority of hematological malignancies. Accordingly, we suggest that YY1 may have important implications as a therapeutic target and as a prognostic biomarker in hematological malignancies. Disclosures No relevant conflicts of interest to declare.
Michael L. Atchison - One of the best experts on this subject based on the ideXlab platform.
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YY1 Is Required for Germinal Center B Cell Development.
PloS one, 2016Co-Authors: Anupam Banerjee, Vishal J. Sindhava, Raja Vuyyuru, Vibha Jha, Suchita Hodewadekar, Tim Manser, Michael L. AtchisonAbstract:YY1 has been implicated as a master regulator of germinal center B cell development as YY1 binding sites are frequently present in promoters of germinal center-expressed genes. YY1 is known to be important for other stages of B cell development including the pro-B and pre-B cells stages. To determine if YY1 plays a critical role in germinal center development, we evaluated YY1 expression during B cell development, and used a YY1 conditional knock-out approach for deletion of YY1 in germinal center B cells (CRE driven by the immunoglobulin heavy chain γ1 switch region promoter; γ1-CRE). We found that YY1 is most highly expressed in germinal center B cells and is increased 3 fold in splenic B cells activated by treatment with anti-IgM and anti-CD40. In addition, deletion of the YY1 gene by action of γ1-CRE recombinase resulted in significant loss of GC cells in both un-immunized and immunized contexts with corresponding loss of serum IgG1. Our results show a crucial role for YY1 in the germinal center reaction.
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Function of YY1 in long-distance DNA interactions
Frontiers Media S.A., 2014Co-Authors: Michael L. AtchisonAbstract: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 are a subject of active investigation. A small number of factors are implicated in controlling Ig locus long-distance interactions including Pax5, 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, ubiquitiation, 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 IgH 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 ubiquitious 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
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increased expression of pcg protein YY1 negatively regulates b cell development while allowing accumulation of myeloid cells and lt hsc cells
PLOS ONE, 2012Co-Authors: Xuan Pan, Morgan Jones, Jie Jiang, Kristina Zaprazna, Warren S Pear, Ivan Maillard, Michael L. AtchisonAbstract:Ying Yang 1 (YY1) is a multifunctional Polycomb Group (PcG) transcription factor that binds to multiple enhancer binding sites in the immunoglobulin (Ig) loci and plays vital roles in early B cell development. PcG proteins have important functions in hematopoietic stem cell renewal and YY1 is the only mammalian PcG protein with DNA binding specificity. Conditional knock-out of YY1 in the mouse B cell lineage results in arrest at the pro-B cell stage, and dosage effects have been observed at various YY1 expression levels. To investigate the impact of elevated YY1 expression on hematopoetic development, we utilized a mouse in vivo bone marrow reconstitution system. We found that mouse bone marrow cells expressing elevated levels of YY1 exhibited a selective disadvantage as they progressed from hematopoietic stem/progenitor cells to pro-B, pre-B, immature B and re-circulating B cell stages, but no disadvantage of YY1 over-expression was observed in myeloid lineage cells. Furthermore, mouse bone marrow cells expressing elevated levels of YY1 displayed enrichment for cells with surface markers characteristic of long-term hematopoietic stem cells (HSC). YY1 expression induced apoptosis in mouse B cell lines in vitro, and resulted in down-regulated expression of anti-apoptotic genes Bcl-xl and NFκB2, while no impact was observed in a mouse myeloid line. B cell apoptosis and LT-HSC enrichment induced by YY1 suggest that novel strategies to induce YY1 expression could have beneficial effects in the treatment of B lineage malignancies while preserving normal HSCs.
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Transcription factor YY1 functions as a PcG protein in vivo
The EMBO journal, 2003Co-Authors: Lakshmi Atchison, Ayesha Ghias, Frank H. Wilkinson, Nancy M. Bonini, Michael L. AtchisonAbstract:Polycomb group (PcG) proteins function as high molecular weight complexes that maintain transcriptional repression patterns during embryogenesis. The vertebrate DNA binding protein and transcriptional repressor, YY1, shows sequence homology with the Drosophila PcG protein, pleiohomeotic (PHO). YY1 might therefore be a vertebrate PcG protein. We used Drosophila embryo and larval/imaginal disc transcriptional repression systems to determine whether YY1 repressed transcription in a manner consistent with PcG function in vivo. YY1 repressed transcription in Drosophila, and this repression was stable on a PcG-responsive promoter, but not on a PcG-non-responsive promoter. PcG mutants ablated YY1 repression, and YY1 could substitute for PHO in repressing transcription in wing imaginal discs. YY1 functionally compensated for loss of PHO in pho mutant flies and partially corrected mutant phenotypes. Taken together, these results indicate that YY1 functions as a PcG protein. Finally, we found that YY1, as well as Polycomb, required the co-repressor protein CtBP for repression in vivo. These results provide a mechanism for recruitment of vertebrate PcG complexes to DNA and demonstrate new functions for YY1.
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Identification of YY1 sequences necessary for association with the nuclear matrix and for transcriptional repression functions
Journal of cellular biochemistry, 1998Co-Authors: Sarah M. Bushmeyer, Michael L. AtchisonAbstract:YY1 is a zinc finger-containing transcription factor that can both repress and activate transcription. YY1 appears to use multiple mechanisms to carry out its diverse functions. Recently, it was observed that YY1 can exist in multiple nuclear compartments. In addition to being present in the nuclear extract fraction, YY1 is also a component of the nuclear matrix. We show that YY1 can be sequestered in vivo into a high-molecular-weight complex and can be dislodged from this complex either by treatment with formamide or by incubation with an oligonucleotide containing the YY1 DNA binding site sequence. By transfecting plasmids expressing various YY1 deletion constructs and subsequent nuclear fractionation, we have identified sequences necessary for association with the nuclear matrix. These sequences (residues 256–340) co-localized with those necessary for in vivo sequestration of YY1 into the high-molecular-weight complex. We have also characterized YY1 sequences necessary for repression of activated transcription (residues 333–371) and those necessary for masking of the YY1 transactivation domain (residues 371–397). Sequences that repress activated transcription partially overlap YY1 sequences necessary for association with the nuclear matrix. However, these sequences are distinct from those that appear to mask the YY1 transactivation domain. The potential role of nuclear matrix association in controlling YY1 function is discussed. J. Cell. Biochem. 68:484–499, 1998. © 1998 Wiley-Liss, Inc.
Xuan Pan - One of the best experts on this subject based on the ideXlab platform.
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YY1 Controls Hematopoietic Stem Cell Quiescence By Repressing Cohesin Expression
Blood, 2018Co-Authors: Anna L. F. V. Assumpção, Aaron D. Viny, Ross L. Levine, Xuan PanAbstract:Abstract Hematopoietic stem cells (HSCs) are undifferentiated, self-renewing, pluripotent cells that have the capacity to differentiate into all mature lineage-specific cells in adult blood. Adult HSCs can remain in a quiescent state for a prolonged time, and quiescence is a fundamental characteristic of HSCs in adult bone marrow. Thus, the cell cycle must be precisely regulated. Yin Yang 1 (YY1) is a multifunctional transcription factor and Polycomb Group Protein (PcG) that is important for embryonic development, adult hematopoiesis, cell proliferation and maintaining higher-order chromosomal structure. We have generated YY1 conditional knockout mice (YY1f/f Mx1-Cre) and showed that YY1 deficient HSCs fail to self-renewal and had disrupted HSCs quiescence. Stem cell factor (SCF)/c-Kit signaling, a critical regulatory pathway in HSC development, is significantly downregulated in YY1-/- HSCs. Interestingly, YY1 regulation of HSCs self-renewal and quiescence is independent on its PcG domain/function. Instead, YY1 occupied at Smc3 promoter area and repressed Smc3 expression. In YY1-/-HSCs, Smc3 expression was upregulated. SMC3 is a core component of cohesin protein complex and plays critical roles in HSC self-renewal, myeloid differentiation and leukemogenesis. To further dissect the underlying mechanisms by which YY1 regulates SMC3 expression in HSCs, we have generated conditional knockout mice with YY1 homozygous deletion and SMC3 heterozygous deletion (YY1f/f Smc3f/+Mx1-Cre). In YY1-/- Smc3+/- bone marrow cells, SMC3 expression was normalized to the wild-type level. In adult bone marrow cells, YY1 physically interacted with cohesin complex proteins through its zinc finger domain. By analyzing the YY1, SMC1A and SMC3 ChIP-Seq database, our study showed that YY1 and cohesin co-occupied at promoter areas of genes that are critical for cell metabolism. Evidence from previous study showed that impaired metabolism, including increased reactive oxygen species (ROS) and decreased mitochondrial function, can cause defect in stem cell self-renewal and quiescence. In YY1-/- Smc3+/-HSCs, cell quiescence was restored although HSC self-renewal was still impaired, indicates that YY1 and SMC3 may control HSC cell quiescence via regulating genes critical for cell metabolism. Our study identified YY1 as the first transcription factor that regulates expression of cohesin complex component SMC3. We are currently further dissecting underlying mechanisms and functional significances of metabolic pathways regulated by YY1-SMC3 axis in HSCs. Disclosures Levine: Imago: Equity Ownership; Isoplexis: Equity Ownership; Janssen: Consultancy, Honoraria; Gilead: Honoraria; Epizyme: Patents & Royalties; Loxo: Consultancy, Equity Ownership; C4 Therapeutics: Equity Ownership; Roche: Consultancy, Research Funding; Prelude: Research Funding; Qiagen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Novartis: Consultancy.
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Polycomb Group Protein YY1 Is an Essential Regulator of Hematopoietic Stem Cell Quiescence
Cell reports, 2018Co-Authors: Courtney C. Hong, Anna L. F. V. Assumpção, Guangyao Kong, Irene M. Ong, Emery H. Bresnick, Jing Zhang, Xuan PanAbstract:Summary Yin yang 1 (YY1) is a ubiquitous transcription factor and mammalian polycomb group protein (PcG) with important functions to regulate embryonic development, lineage differentiation, and cell proliferation. YY1 mediates stable PcG-dependent transcriptional repression via recruitment of PcG proteins that catalyze histone modifications. Many questions remain unanswered regarding how cell- and tissue-specificity is achieved by PcG proteins. Here, we demonstrate that a conditional knockout of YY1 in hematopoietic stem cells (HSCs) decreases long-term repopulating activity and ectopic YY1 expression expands HSCs. Although the YY1 PcG domain is required for Igκ chain rearrangement in B cells, the YY1 mutant lacking the PcG domain retained the capacity to stimulate HSC self-renewal. YY1 deficiency deregulated the genetic network governing HSC cell proliferation and impaired stem cell factor/c-Kit signaling, disrupting mechanisms conferring HSC quiescence. These results reveal a mechanism for how a ubiquitously expressed transcriptional repressor mediates lineage-specific functions to control adult hematopoiesis.
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YY1 controls igκ repertoire and b cell development and localizes with condensin on the igκ locus
The EMBO Journal, 2013Co-Authors: Xuan Pan, Madhusudhan Papasani, Yi Hao, Marco Calamito, Fang Wei, William J Quinn, Arindam Basu, Junwen Wang, Suchita Hodawadekar, Kristina ZapraznaAbstract: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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increased expression of pcg protein YY1 negatively regulates b cell development while allowing accumulation of myeloid cells and lt hsc cells
PLOS ONE, 2012Co-Authors: Xuan Pan, Morgan Jones, Jie Jiang, Kristina Zaprazna, Warren S Pear, Ivan Maillard, Michael L. AtchisonAbstract:Ying Yang 1 (YY1) is a multifunctional Polycomb Group (PcG) transcription factor that binds to multiple enhancer binding sites in the immunoglobulin (Ig) loci and plays vital roles in early B cell development. PcG proteins have important functions in hematopoietic stem cell renewal and YY1 is the only mammalian PcG protein with DNA binding specificity. Conditional knock-out of YY1 in the mouse B cell lineage results in arrest at the pro-B cell stage, and dosage effects have been observed at various YY1 expression levels. To investigate the impact of elevated YY1 expression on hematopoetic development, we utilized a mouse in vivo bone marrow reconstitution system. We found that mouse bone marrow cells expressing elevated levels of YY1 exhibited a selective disadvantage as they progressed from hematopoietic stem/progenitor cells to pro-B, pre-B, immature B and re-circulating B cell stages, but no disadvantage of YY1 over-expression was observed in myeloid lineage cells. Furthermore, mouse bone marrow cells expressing elevated levels of YY1 displayed enrichment for cells with surface markers characteristic of long-term hematopoietic stem cells (HSC). YY1 expression induced apoptosis in mouse B cell lines in vitro, and resulted in down-regulated expression of anti-apoptotic genes Bcl-xl and NFκB2, while no impact was observed in a mouse myeloid line. B cell apoptosis and LT-HSC enrichment induced by YY1 suggest that novel strategies to induce YY1 expression could have beneficial effects in the treatment of B lineage malignancies while preserving normal HSCs.
Yang Shi - One of the best experts on this subject based on the ideXlab platform.
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a YY1 ino80 complex regulates genomic stability through homologous recombination based repair
Nature Structural & Molecular Biology, 2007Co-Authors: Huifei Liu, Yujiang Shi, Peter Mulligan, Joseph Landry, Weijia Wang, Jac A Nickoloff, Yang ShiAbstract:DNA damage repair is crucial for the maintenance of genome integrity and cancer suppression. We found that loss of the mouse transcription factor YY1 resulted in polyploidy and chromatid aberrations, which are signatures of defects in homologous recombination. Further biochemical analyses identified a YY1 complex comprising components of the evolutionarily conserved INO80 chromatin-remodeling complex. Notably, RNA interference–mediated knockdown of YY1 and INO80 increased cellular sensitivity toward DNA-damaging agents. Functional assays revealed that both YY1 and INO80 are essential in homologous recombination–based DNA repair (HRR), which was further supported by the finding that YY1 preferentially bound a recombination-intermediate structure in vitro. Collectively, these observations reveal a link between YY1 and INO80 and roles for both in HRR, providing new insight into mechanisms that control the cellular response to genotoxic stress.
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YY1 functions with INO80 to activate transcription.
Nature structural & molecular biology, 2007Co-Authors: Yong Cai, Yang Shi, Jingji Jin, Tingting Yao, Aaron J. Gottschalk, Selene K. Swanson, Michael P. Washburn, Laurence Florens, Ronald C. ConawayAbstract:Ubiquitously expressed transcription factor Yin-Yang-1 (YY1) controls expression of many genes. YY1 is tightly associated with the human ATP-dependent INO80-like chromatin-remodeling complex (INO80). INO80 is recruited by YY1 to YY1-activated genes, where it functions as an essential coactivator. Binding of YY1 to its DNA sites in target genes requires INO80, suggesting that YY1 uses the INO80 complex not only to activate transcription but also to gain access to target promoters.
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the human factors YY1 and lsf repress the human immunodeficiency virus type 1 long terminal repeat via recruitment of histone deacetylase 1
Journal of Virology, 2000Co-Authors: Jason J Coull, Katherine Galvin, Yang Shi, Fabio Romerio, Jianmin Sun, Janet Volker, James R Davie, Ulla Hansen, David M MargolisAbstract:Enigmatic mechanisms restore the resting state in activated lymphocytes following human immunodeficiency virus type 1 (HIV-1) infection, rarely allowing persistent nonproductive infection. We detail a mechanism whereby cellular factors could establish virological latency. The transcription factors YY1 and LSF cooperate in repression of transcription from the HIV-1 long terminal repeat (LTR). LSF recruits YY1 to the LTR via the zinc fingers of YY1. The first two zinc fingers were observed to be sufficient for this interaction in vitro. A mutant of LSF incapable of binding DNA blocked repression. Like other transcriptional repressors, YY1 can function via recruitment of histone deacetylase (HDAC). We find that HDAC1 copurifies with the LTR-binding YY1-LSF repressor complex, the domain of YY1 that interacts with HDAC1 is required to repress the HIV-1 promoter, expression of HDAC1 augments repression of the LTR by YY1, and the deacetylase inhibitor trichostatin A blocks repression mediated by YY1. This novel link between HDAC recruitment and inhibition of HIV-1 expression by YY1 and LSF, in the natural context of a viral promoter integrated into chromosomal DNA, is the first demonstration of a molecular mechanism of repression of HIV-1. YY1 and LSF may establish transcriptional and virological latency of HIV, a state that has recently been recognized in vivo and has significant implications for the long-term treatment of AIDS.
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MULTIPLE MECHANISMS OF TRANSCRIPTIONAL REPRESSION BY YY1
Molecular and cellular biology, 1997Co-Authors: Katherine Galvin, Yang ShiAbstract:The four C-terminal GLI-Kruppel type zinc fingers of YY1 have been identified as a transcriptional repression domain. Previous reports have proposed DNA-bending and activator-quenching mechanisms for this zinc finger-mediated repression. In addition, previous work indicated that p300 and CBP might be involved in YY1-mediated repression. We have analyzed these possible models for the zinc finger-mediated repression. The role of each zinc finger in the repression and DNA-binding functions was determined by using a structure-and-function approach. We show that zinc finger 2 of YY1 plays a central role in both DNA binding and transcriptional repression. However, a survey of a panel of YY1 mutants indicates that these two functions can be separated, which argues against the DNA-bending model for repression. We show that the physical interaction between YY1 and p300, a coactivator for CREB, is not sufficient for repression of CREB-mediated transcription. Our studies indicate that YY1 functions as an activator-specific repressor. Repression of CTF-1-directed transcription may be accomplished through direct physical interaction between YY1 and this activator. In contrast, physical interaction is not necessary for YY1 to repress Sp1- and CREB-mediated transcription. Rather, the repression likely reflects an ability of YY1 to interfere with communication between these activators and their targets within the general transcription machinery. Taken together, our results suggest that YY1 employs multiple mechanisms to achieve activator-specific repression.
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Relief of YY1 transcriptional repression by adenovirus E1A is mediated by E1A-associated protein p300.
Genes & development, 1995Co-Authors: Jeng-shin Lee, Raymond H. See, Katherine Galvin, Richard Eckner, David M. Livingston, E Moran, Yang ShiAbstract:YY1 represses transcription when bound upstream of transcriptional initiation sites. This repression can be relieved by adenovirus E1A. Here, we present genetic evidence that the ability of E1A to relieve YY1 repression was impaired by mutations that affect E1A binding to its associated protein p300. This suggests that E1A may modulate the repressor activity of YY1 by binding to p300, which may be physically complexed with YY1. A YY1/p300 protein complex in vivo was demonstrated by several independent approaches, and the YY1-interacting domain was mapped to the carboxy-terminal region of p300, distinct from the E1A-binding site. Unlike E2F/RB, the YY1/p300 complex is not disrupted by E1A. Functional studies using recombinant p300 demonstrated unequivocally that p300 is capable of mediating E1A-induced transcriptional activation through YY1. Taken together, these results reveal, for the first time, a YY1/p300 complex that is targeted by E1A and demonstrate a function for p300 in mediating interactions between YY1 and E1A. Our data thus identify YY1 as a partner protein for p300 and uncover a molecular mechanism for the relief of YY1-mediated repression by E1A.
Joomyeong Kim - One of the best experts on this subject based on the ideXlab platform.
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YY1's DNA-binding motifs in mammalian olfactory receptor genes.
BMC Genomics, 2009Co-Authors: Christopher Faulk, Joomyeong KimAbstract:YY1 is an epigenetic regulator for a large number of mammalian genes. While performing genome-wide YY1 binding motif searches, we discovered that the olfactory receptor (OLFR) genes have an unusual cluster of YY1 binding sites within their coding regions. The statistical significance of this observation was further analyzed. About 45% of the olfactory genes in the mouse have a range of 4-8 YY1 binding sites within their respective 1 kb coding regions. Statistical analyses indicate that this enrichment of YY1 motifs has likely been driven by unknown selection pressures at the DNA level, but not serendipitously by some peptides enriched within the OLFR genes. Similar patterns are also detected in the OLFR genes of all mammals analyzed, but not in the OLFR genes of the fish lineage, suggesting a mammal-specific phenomenon. YY1, or YY1-related transcription factors, may help regulate olfactory receptor genes. Furthermore, the protein-coding regions of vertebrate genes can contain cis-regulatory elements for transcription factor binding as well as codons.
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YY1's role in DNA methylation of Peg3 and Xist
Nucleic acids research, 2009Co-Authors: Jeong Do Kim, Keunsoo Kang, Joomyeong KimAbstract:Unusual clusters of YY1 binding sites are located within several differentially methylated regions (DMRs), including Xist, Nespas and Peg3, which all become methylated during oogenesis. In this study, we performed conditional YY1 knockdown (KD) to investigate YY1's roles in DNA methylation of these DMRs. Reduced levels of YY1 during spermatogenesis did not cause any major change in these DMRs although the same YY1 KD caused hypermethylation in these DMRs among a subset of aged mice. However, YY1 KD during oogenesis resulted in the loss of DNA methylation on Peg3 and Xist, but there were no changes on Nespas and H19. Continued YY1 KD from oogenesis to the blastocyst stage caused further loss in DNA methylation on Peg3. Consequently, high incidents of lethality were observed among embryos that had experienced the reduced levels of YY1 protein. Overall, the current study suggests that YY1 likely plays a role in the de novo DNA methylation of the DMRs of Peg3 and Xist during oogenesis and also in the maintenance of unmethylation status of these DMRs during spermatogenesis.
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YY1's longer DNA-binding motifs.
Genomics, 2008Co-Authors: Jeong Do Kim, Joomyeong KimAbstract:The DNA-binding sites of YY1 located within two newly identified downstream genes of YY1, Peg3 (GGCGCCATnTT) and Xist (CCGCCATnTT), are longer than the known motif of YY1 (CGCCATnTT). Gel shift assays indicated that these DNA-binding sites are previously unnoticed, longer motifs of YY1. Independent DNA-binding motif studies further confirmed that YY1 recognizes a longer sequence (GCCGCCATTTTG) as its consensus motif. This longer motif exhibited higher affinity to the YY1 protein than the known motif. Another DNA-binding motif study was also performed using a protein containing three amino acid substitutions in the first zinc finger unit of YY1, mimicking the zinc finger domain of pho (a drosophila homologue of YY1). The substitutions cause the weakening of DNA-binding specificity at both 5'- and 3'-sides of the longer motif, yielding a much shorter sequence (GCCAT) as a consensus motif. This indicates that the intact first finger unit is required for recognition of the longer motif of YY1. Also, this shortening suggests that the DNA recognition by YY1 is mediated through the concerted, but not modular, contribution by its four zinc finger units.
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Identification of clustered YY1 binding sites in imprinting control regions.
Genome research, 2006Co-Authors: Jeong Do Kim, Angela K. Hinz, Anne Bergmann, Jennifer M. Huang, Ivan Ovcharenko, Lisa Stubbs, Joomyeong KimAbstract:Mammalian genomic imprinting is regulated by imprinting control regions (ICRs) that are usually associated with tandem arrays of transcription factor binding sites. In this study, the sequence features derived from a tandem array of YY1 binding sites of Peg3-DMR (differentially methylated region) led us to identify three additional clustered YY1 binding sites, which are also localized within the DMRs of Xist, Tsix, and Nespas. These regions have been shown to play a critical role as ICRs for the regulation of surrounding genes. These ICRs have maintained a tandem array of YY1 binding sites during mammalian evolution. The in vivo binding of YY1 to these regions is allele specific and only to the unmethylated active alleles. Promoter/enhancer assays suggest that a tandem array of YY1 binding sites function as a potential orientation-dependent enhancer. Insulator assays revealed that the enhancer-blocking activity is detected only in the YY1 binding sites of Peg3-DMR but not in the YY1 binding sites of other DMRs. Overall, our identification of three additional clustered YY1 binding sites in imprinted domains suggests a significant role for YY1 in mammalian genomic imprinting.
