Yin Yang 1 Research Articles

Hepatic expression of Yin Yang 1 (YY1) is associated with the non-alcoholic fatty liver disease (NAFLD) progression in patients undergoing bariatric surgery

BackgroundThis study is to investigate the association between the hepatic expression of Yin Yang 1 (YY1) and the progression of non-alcoholic fatty liver disease (NAFLD) in patients undergoing bariatric surgery.MethodsObese patients undergoing bariatric surgery were included. Liver tissues were subjected to the quantitative real-time PCR, Western blot analysis, and immunohistochemical assay, to determine the expression levels of YY1.ResultsTotally 88 patients were included. According to the NAFLD activity score (NAS), these patients were divided into the control (n = 12), steatosis (n = 20), non-defining NASH (n = 38), and NASH (n = 18) groups. Significant differences in the serum glucose, insulin, ALT, AST, and HOMA-IR levels were observed among these different NAFLD groups. Hepatic YY1 expression had correlation with serum glucose, insulin, HOMA-IR, ALT, AST, triglycerides, HDL, and GGT. Immunohistochemical analysis showed that, compared with the control group, the expression levels of YY1 were significantly higher in the non-defining NASH and NASH groups. In addition, multivariate regression model showed that the serum ALT and YY1 levels were strongly associated with the NAFLD activity.ConclusionsSeveral factors are associated with NAFLD progression, including the expression of YY1. Our findings contribute to understanding of the pathogenesis of NAFLD.Trial registrationNCT03296605, registered on September 28, 2017.

Oxidative stress-elicited YY1 potentiates antioxidative response via enhancement of NRF2-driven transcriptional activity: A potential neuronal defensive mechanism against ischemia/reperfusion cerebral injury.

Cerebral ischemia challenge evokes an adaptive defensive system through the induction of antioxidant enzymes. Many of such antioxidant enzymes are regulated essentially by the nuclear factor erythroid 2-related factor-2 (NRF2). Compelling evidence supports that targeting NRF2 signaling is a promising therapeutic strategy to alleviate post-I/R brain injury, but the molecular mechanisms underlying this strategy have yet to be elucidated. Herein, we show that the expression of transcription factor Yin Yang 1 (YY1) is significantly upregulated during the recovery following middle cerebral artery occlusion (MCAO). Ablation of endogenous YY1 using cerebral ventricle injection of siRNA exacerbated I/R-induced neuronal damage and attenuated the antioxidant defensive system. Mechanistically, low levels of reactive oxygen species (ROS) production stimulated neuronal YY1 expression, whereas high levels of ROS exhibited a noticeable inhibitory effect. The evoked YY1, in concert with other coregulators, recruited to the antioxidant responsive elements (AREs) binding site and then amplified the NRF2-mediated ARE transcription, thereby protecting cells against damage by potentiating antioxidant response. In this regard, compromise of YY1 expression by ROS overactivity is an important etiology that sabotages the antioxidant defensive system and consequently deteriorate s neuronal damage following I/R injury. Taken together, our findings provide novel evidence on a delicate and synergistical collaboration between YY1 and the master transcription factor NRF2 that functions to mobilize the cell's antioxidant machinery.

Transcription Factor YY1 Promotes Cell Proliferation by Directly Activating the Pentose Phosphate Pathway.

Tumor cells alter their metabolism to meet their demand for macromolecules and support a high rate of proliferation as well as cope with oxidative stress. The transcription factor yin yang 1 (YY1) is upregulated in various types of tumors and is crucial for tumor cell proliferation and metastasis. However, its role in tumor cell metabolic reprogramming is poorly understood. Here, we show that YY1 alters tumor cell metabolism by activating glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway. By stimulating the pentose phosphate pathway, YY1 enhanced production of nucleotides and DNA synthesis, decreased intracellular reactive oxygen species levels, and promoted antioxidant defense by supplying increased reducing power in the form of NADPH. Importantly, YY1-mediated regulation of the pentose phosphate pathway in tumor cells occurred not through p53, but rather through direct activation of G6PD transcription by YY1. Regulation of pentose phosphate pathway activity through G6PD was strongly related to YY1-induced proliferation of tumor cells and tumorigenesis. Together, our results describe a novel role for YY1 in regulating G6PD in a p53-independent manner, which links its function in tumorigenesis to metabolic reprogramming in tumor cells.Significance: This study reveals a novel role for YY1 in regulating G6PD and activating the pentose phosphate pathway, linking its function in tumorigenesis to metabolic reprogramming. Cancer Res; 78(16); 4549-62. ©2018 AACR.

Planar cell polarity gene Fuz triggers apoptosis in neurodegenerative disease models.

Planar cell polarity (PCP) describes a cell-cell communication process through which individual cells coordinate and align within the plane of a tissue. In this study, we show that overexpression of Fuz, a PCP gene, triggers neuronal apoptosis via the dishevelled/Rac1 GTPase/MEKK1/JNK/caspase signalling axis. Consistent with this finding, endogenous Fuz expression is upregulated in models of polyglutamine (polyQ) diseases and in fibroblasts from spinocerebellar ataxia type 3 (SCA3) patients. The disruption of this upregulation mitigates polyQ-induced neurodegeneration in Drosophila We show that the transcriptional regulator Yin Yang 1 (YY1) associates with the Fuz promoter. Overexpression of YY1 promotes the hypermethylation of Fuz promoter, causing transcriptional repression of Fuz Remarkably, YY1 protein is recruited to ATXN3-Q84 aggregates, which reduces the level of functional, soluble YY1, resulting in Fuz transcriptional derepression and induction of neuronal apoptosis. Furthermore, Fuz transcript level is elevated in amyloid beta-peptide, Tau and α-synuclein models, implicating its potential involvement in other neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. Taken together, this study unveils a generic Fuz-mediated apoptotic cell death pathway in neurodegenerative disorders.

Yin Yang 1 promotes the Warburg effect and tumorigenesis via glucose transporter GLUT3.

Cancer cells typically shift their metabolism to aerobic glycolysis to fulfill the demand of energy and macromolecules to support their proliferation. Glucose transporter (GLUT) family‐mediated glucose transport is the pacesetter of aerobic glycolysis and, thus, is critical for tumor cell metabolism. Yin Yang 1 (YY1) is an oncogene crucial for tumorigenesis; however, its role in tumor cell glucose metabolism remains unclear. Here, we revealed that YY1 activates GLUT3 transcription by directly binding to its promoter and, concomitantly, enhances tumor cell aerobic glycolysis. This regulatory effect of YY1 on glucose entry into the cells is critical for YY1‐induced tumor cell proliferation and tumorigenesis. Intriguingly, YY1 regulation of GLUT3 expression, and, subsequently, of tumor cell aerobic glycolysis and tumorigenesis, occurs p53‐independently. Our results also showed that clinical drug oxaliplatin suppresses colon carcinoma cell proliferation by inhibiting the YY1/GLUT3 axis. Together, these results link YY1's tumorigenic potential with the critical first step of aerobic glycolysis. Thus, our novel findings not only provide new insights into the complex role of YY1 in tumorigenesis but also indicate the potential of YY1 as a target for cancer therapy irrespective of the p53 status.

BCCIP binds to and activates its promoter in a YY1-dependent fashion in HCT116 cells.

The restriction of Yin Yang 1 (YY1) at BRCA2 and CDKN1A/p21-interacting protein (BCCIP) transcriptional start site (TSS) proximal region in several human cancer cell lines was found by analyzation of ChIP-Seq database from UCSC Genome Browser (http://genome.ucsc.edu). However, whether the stabilization of YY1 by BCCIP impacts its recruitment in the BCCIP promoter region is unclear. Here, we present evidence that transcriptional regulation of YY1 on BCCIP is closely related to YY1 stability in HCT116 human colon cancer cells. YY1 stabilization was in turn regulated by BCCIP, suggesting the existence of a BCCIP-YY1 feedback loop in regulating BCCIP transcription by the YY1. Overexpression of BCCIP stabilized YY1 while knockdown of BCCIP reduced YY1 protein level. In addition, direct interaction between YY1 and BCCIP was confirmed by coimmunoprecipitation approach. Also, the N-terminus region of BCCIP, including the internal conserved domain (ICD), was responsible for binding with the amino acid 146-270 of YY1. More importantly, YY1 stability was related to the BCCIP/ICD domain-mediated YY1 ubiquitination pathway. Moreover, a limited BCCIP promoter region containing YY1 binding site (CCGCCATC) was tightly associated with the pGL4-BCCIP-Luc luciferase activity. In ChIP assays, shBCCIP lentiviral-mediated YY1 instability decreased recruitment of the YY1 at BCCIP TSS proximal region, which could not be restored by YY1 overexpression. Furthermore, knockdown of YY1 inhibited the binding of BCCIP itself at BCCIP promoter region proximal to TSS, demonstrating that transcriptional regulation of the YY1 on BCCIP can be modulated by BCCIP itself in a YY1-dependent fashion.

Knockdown of Yin Yang 1 enhances anticancer effects of cisplatin through protein phosphatase 2A-mediated T308 dephosphorylation of AKT

Cisplatin is still one of the first-line drugs for chemotherapy of head and neck squamous cell carcinoma (HNSCC) and shows a survival advantage for HNSCC. However, a substantial proportion of HNSCC eventually becomes resistance to cisplatin and the underlying mechanisms remain to be fully understood. Yin Yang 1 (YY1) is a multifunctional protein regulating both gene transcription and protein modifications and also plays a role in chemotherapy resistance. Here, we reported that knockdown of YY1 by lentivirus-mediated short hairpin RNA or tetracycline-inducible short hairpin RNA enhanced cisplatin-induced apoptosis and inhibition of cell proliferation, migration and invasion in the HNSCC cell lines, and inhibition of the xenograft tumor growth. The underlying mechanisms were revealed that knockdown of YY1 downregulated both S473 and T308 phosphorylation of AKT (protein kinase B), which was mainly responsible for cisplatin resistance, whereas overexpression of YY1 upregulated both S473 and T308 phosphorylation. Cisplatin upregulated YY1 mRNA and protein expression and both S473 and T308 phosphorylation of AKT. In the presence of cisplatin, knockdown of YY1 not only blocked cisplatin-induced increase in S473 and T308 phosphorylation of AKT, but still downregulated T308 phosphorylation. Moreover, protein phosphatase 2A (PP2A) antagonist, okadaic acid, upregulated T308, but not S473, phosphorylation, and simultaneously abolished YY1 knockdown-mediated enhancement of cisplatin-induced inhibition of cell proliferation. In addition, knockdown of YY1 promoted PP2A activity through upregulating mRNA and protein expressions of PP2A catalytic subunit alpha (PPP2CA) through the binding of YY1 in the promoter of PPP2CA. Conversely, activating PP2A by forskolin also promoted YY1 degradation and subsequently inhibited T308 phosphorylation. These results suggested that knockdown of YY1 enhanced anticancer effects of cisplatin through PP2A mediating T308 dephosphorylation of AKT, and that targeting YY1 or PP2A would enhance the efficiency of cisplatin chemotherapy in treatment of HNSCC.

MiR-147b influences vascular smooth muscle cell proliferation and migration via targeting YY1 and modulating Wnt/β-catenin activities.

Cardiovascular disease is the leading cause of death worldwide. Dysregulation of microRNAs (miRNAs) has been found to be associated with cardiovascular diseases such as atherosclerosis. In the present study, we examined the role of miR-147b in the proliferation and migration of vascular smooth muscle cells (VSMCs). Quantitative real-time PCR was performed to determine the expression levels of miR-147b and Yin Yang 1 (YY1) mRNA. CCK-8, transwell migration and wound healing assays were used to determine cell proliferation and migration of VSMCs, respectively. Luciferase reporter assay confirmed the downstream target of miR-147b. The protein level of YY1 was measured by western blot analysis. Platelet-derived growth factor-bb (PDGF-bb) treatment promoted cell proliferation and increased miR-147b expression in VSMCs. Overexpression of miR-147b enhanced cell proliferation and migration of VSMCs, while knock-down of miR-147b suppressed cell proliferation and migration of VSMCs or PDGF-bb-treated VSMCs. Further, bioinformatics prediction and luciferase reporter assay showed that YY1 was a downstream target of miR-147b, and miR-147b negatively regulated the mRNA and protein expression of YY1 in VSMCs. Overexpression of YY1 inhibited cell proliferation and migration of VSMCs and attenuated the effects of miR-147b overexpression on cell proliferation and migration. In addition, overexpression of miR-147b increased the Wnt/β-catenin signaling activities in VSMCs. In conclusion, our results suggest that miR-147b plays important roles in the control of cell proliferation and migration of VSMCs possibly via targeting YY1.

Abstract 358: miRNAs/Ago2/YY1/PcG protein/DNMT complex mediates epigenetic silencing of locus genes and associates with bortezomib-induced apoptosis of leukemia

Abstract miRNAs are a class of non-coding RNAs, which bind to the 3'-untranslated regions of their target mRNAs to repress translation. However, the details of miRNA-mediated epigenetic regulation targeting genomic DNA remained largely unknown. Here, we demonstrated that transcription factor CCAAT/enhancer binding protein delta (CEBPD) was responsive to the anticancer drug bortezomib, is a highly selective reversible inhibitor for leukemia treatment, and resulting in caspase activation and apoptosis. Interestingly, following the identification of CEBPD-induced miRNAs, we found that miR-744, miR-3154 and miR-3162 feedback to suppress the transcription of CEBPD itself and genes adjacent to its 5'-flanking region, including protein kinase DNA-activated catalytic polypeptide (PRKDC), minichromosome maintenance-deficient 4 (MCM4) and ubiquitin-conjugating enzyme E2 variant 2 (UBE2V2), upon bortezomib treatment. Additionally, we previously demonstrated that the Yin Yang 1 (YY1)/polycomb group (PcG) protein/DNA methyltransferase (DNMT) complex is important for mediating epigenetic silencing of the CEBPD gene; we further found that Argonaute 2 (Ago2) interacts with YY1 and binds to the CEBPD promoter. Moreover, we revealed that miRNA binding plays a key role for YY1/PcG group protein/DNMT complex-mediated epigenetic gene silencing and is associated with bortezomib-induced methylation on genomic DNA. Altogether, we provided new insights for miRNA-mediated epigenetic regulation in the case of bortezomib-induced cell death in leukemia. Citation Format: Ju-Ming Wang, Yu-Yi Chu, Chiung-Yuan Ko, Shao-Ming Wang, Pin-I Lin, Han-Ying Wang, Wen-Chi Lin, Dong-Yu Wu. miRNAs/Ago2/YY1/PcG protein/DNMT complex mediates epigenetic silencing of locus genes and associates with bortezomib-induced apoptosis of leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 358.

A regulatory mutant on TRIM26 conferring the risk of nasopharyngeal carcinoma by inducing low immune response.

The major histocompatibility complex (MHC) is most closely associated with nasopharyngeal carcinoma (NPC), but the complexity of its genome structure has proven challenging for the discovery of causal MHC loci or genes. We conducted a targeted MHC sequencing in 40 Cantonese NPC patients followed by a two‐stage replication in 1065 NPC cases and 2137 controls of Southern Chinese descendent. Quantitative RT‐PCR analysis (qRT‐PCR) was used to detect gene expression status in 108 NPC and 43 noncancerous nasopharyngeal (NP) samples. Luciferase reporter assay and chromatin immunoprecipitation (ChIP) were used to assess the transcription factor binding site. We discovered that a novel SNP rs117565607_A at TRIM26 displayed the strongest association (OR = 1.909, Pcombined = 2.750 × 10−19). We also observed that TRIM26 was significantly downregulated in NPC tissue samples with genotype AA/AT than TT. Immunohistochemistry (IHC) test also found the TRIM26 protein expression in NPC tissue samples with the genotype AA/AT was lower than TT. According to computational prediction, rs117565607 locus was a binding site for the transcription factor Yin Yang 1 (YY1). We observed that the luciferase activity of YY1 which is binding to the A allele of rs117565607 was suppressed. ChIP data showed that YY1 was binding with T not A allele. Significance analysis of microarray suggested that TRIM26 downregulation was related to low immune response in NPC. We have identified a novel gene TRIM26 and a novel SNP rs117565607_A associated with NPC risk by regulating transcriptional process and established a new functional link between TRIM26 downregulation and low immune response in NPC.

YY1 promotes IL-6 expression in LPS-stimulated BV2 microglial cells by interacting with p65 to promote transcriptional activation of IL-6

Neuroinflammation plays a critical role in the process of neurodegenerative disorders, during which microglia, the principal resident immune cells in the central nervous system, are activated and produce proinflammatory mediators. Yin-Yang 1 (YY1), a multi-functional transcription factor, is widely expressed in cells of the immune system and participate in various cellular processes. However, whether YY1 is involved in the process of neuroinflammation is still unknown. In the present study, we found that YY1 was progressively up-regulated in BV2 microglial cells stimulated with lipopolysaccharide (LPS), which was dependent on the transactivation function of nuclear factor kappa B (NF-κB). Furthermore, YY1 knockdown notably inhibited LPS-induced the activation of NF-κB signaling and interleukin-6 (IL-6) expression in BV-2 cells, but not mitogen-activated protein kinase (MAPK) signaling. Moreover, YY1 strengthened p65 binding to IL-6 promoter by interacting with p65 but decreased H3K27ac modification on IL-6 promoter, eventually increasing IL-6 transcription. Taken together, these results for the first time uncover the regulatory mechanism of YY1 on IL-6 expression during neuroinflammation responses and provide new lights into neuroinflammation.

C-Abl phosphorylation of Yin Yang 1's conserved tyrosine 254 in the spacer region modulates its transcriptional activity

Yin Yang 1 (YY1) is a multifunctional transcription factor that can activate or repress transcription depending on the promotor and/or the co-factors recruited. YY1 is phosphorylated in various signaling pathways and is critical for different biological functions including embryogenesis, apoptosis, proliferation, cell-cycle regulation and tumorigenesis. Here we report that YY1 is a substrate for c-Abl kinase phosphorylation at conserved residue Y254 in the spacer region. Pharmacological inhibition of c-Abl kinase by imatinib, nilotinib and GZD824, knock-down of c-Abl using siRNA, and the use of c-Abl kinase-dead drastically reduces tyrosine phosphorylation of YY1. Both radioactive and non-radioactive in vitro kinase assays, as well as co-immunoprecipitation in different cell lines, show that the target of c-Abl phosphorylation is tyrosine residue 254. c-Abl phosphorylation has little effect on YY1 DNA binding ability or cellular localization in asynchronous cells. However, functional studies reveal that c-Abl mediated phosphorylation of YY1 regulates YY1's transcriptional ability in vivo. In conclusion, we demonstrate the novel role of c-Abl kinase in regulation of YY1's transcriptional activity, linking YY1 regulation with c-Abl tyrosine kinase signaling pathways.

Conserved RNA binding activity of a Yin-Yang 1 homologue in the ova of the purple sea urchin Strongylocentrotus purpuratus

Yin-Yang 1 (YY1) is a highly conserved transcription factor possessing RNA-binding activity. A putative YY1 homologue was previously identified in the developmental model organism Strongylocentrotus purpuratus (the purple sea urchin) by genomic sequencing. We identified a high degree of sequence similarity with YY1 homologues of vertebrate origin which shared 100% protein sequence identity over the DNA- and RNA-binding zinc-finger region with high similarity in the N-terminal transcriptional activation domain. SpYY1 demonstrated identical DNA- and RNA-binding characteristics between Xenopus laevis and S. purpuratus indicating that it maintains similar functional and biochemical properties across widely divergent deuterostome species. SpYY1 binds to the consensus YY1 DNA element, and also to U-rich RNA sequences. Although we detected SpYY1 RNA-binding activity in ova lysates and observed cytoplasmic localization, SpYY1 was not associated with maternal mRNA in ova. SpYY1 expressed in Xenopus oocytes was excluded from the nucleus and associated with maternally expressed cytoplasmic mRNA molecules. These data demonstrate the existence of an YY1 homologue in S. purpuratus with similar structural and biochemical features to those of the well-studied vertebrate YY1; however, the data reveal major differences in the biological role of YY1 in the regulation of maternally expressed mRNA in the two species.

Astrocyte elevated gene-1 is a novel regulator of astrogliosis and excitatory amino acid transporter-2 via interplaying with nuclear factor-κB signaling in astrocytes from amyotrophic lateral sclerosis mouse model with hSOD1G93A mutation

AEG-1 has received extensive attention on cancer research. However, little is known about its roles in astrogliosis of Amyotrophic lateral sclerosis (ALS). In this study, we detected AEG-1 expression in hSOD1G93A-positive (mut-SOD1) astrocytes and wild type (wt-SOD1) astrocytes, and intend to elucidate its potential functions in ALS related astrogliosis and the always accompanied dysregulated glutamate clearance. Results showed elevated protein and mRNA levels of AEG-1 in mut-SOD1 astrocytes; Also, NF-κB signaling pathway related proteins and inflammatory cytokines were upregulated in mut-SOD1 astrocytes; AEG-1 knockdown attenuated astrocytes proliferation and pro-inflammatory release; also we found that AEG-1 silence inhibited translocation of p65 from cytoplasma to nuclear, which was associated with inhibited NF-κB signaling. Besides, excitatory amino acid transporter-2 (EAAT2) expression levels were significantly decreased, accompanied by impaired glutamate clearance ability, in mut-SOD1 astrocytes; yin yang 1 (YY1), a transcriptional inhibitor for EAAT2, increased in nucleus of mut-SOD1 astrocytes. AEG-1 silence inhibited translocation of YY1 to nucleus, increased EAAT2 expression levels, and enhanced astrocytic ability of glutamate clearance, ultimately exerted the neuronal protection. Findings from this study implicate potential function of AEG-1 in mut-SOD1 related astrogliosis and the accompanied excitatory cytotoxic mechanism in ALS.

MiR-34a-mediated regulation of XIST in female cells under inflammation.

BackgroundEvidence is overwhelming for sex differences in pain, with women representing the majority of the chronic pain patient population. There is a need to explore novel avenues to elucidate this sex bias in the development of chronic inflammatory pain conditions. Complex regional pain syndrome (CRPS) is a chronic neuropathic pain disorder, and the incidence of CRPS is greater in women than in men by ~4:1. Since neurogenic inflammation is a key feature of CRPS, dysregulation of inflammatory responses can be a factor in predisposing women to chronic pain.MethodsOur studies investigating alterations in circulating microRNAs (miRNAs) in whole blood from female CRPS patients showed significant differential expression of miRNAs between responders and poor responders to ketamine treatment. Several of these miRNAs are predicted to target the long noncoding RNA, X-inactive-specific transcript (XIST). XIST mediates X-chromosome inactivation and is essential for equalizing the expression of X-linked genes between females and males. Based on the well-established role in inflammatory process, we focused on miR-34a, one of the miRNAs predicted to target XIST, and downregulated in CRPS patients responding poorly to ketamine.ResultsOur in vitro and in vivo models of acute inflammation and data from patients with CRPS showed that miR-34a can regulate XIST under inflammation directly, and through pro-inflammatory transcription factor Yin-Yang 1 (YY1). XIST was significantly upregulated in a subset of CRPS patients responding poorly to ketamine.ConclusionSince dysregulation of XIST can result in genes escaping inactivation or reactivation in female cells, further investigations on the role of XIST in the predominance of chronic inflammatory and pain disorders in women is warranted.

Histone H4 acetylation regulates behavioral inter-individual variability in zebrafish

BackgroundAnimals can show very different behaviors even in isogenic populations, but the underlying mechanisms to generate this variability remain elusive. We use the zebrafish (Danio rerio) as a model to test the influence of histone modifications on behavior.ResultsWe find that laboratory and isogenic zebrafish larvae show consistent individual behaviors when swimming freely in identical wells or in reaction to stimuli. This behavioral inter-individual variability is reduced when we impair the histone deacetylation pathway. Individuals with high levels of histone H4 acetylation, and specifically H4K12, behave similarly to the average of the population, but those with low levels deviate from it. More precisely, we find a set of genomic regions whose histone H4 acetylation is reduced with the distance between the individual and the average population behavior. We find evidence that this modulation depends on a complex of Yin-yang 1 (YY1) and histone deacetylase 1 (HDAC1) that binds to and deacetylates these regions. These changes are not only maintained at the transcriptional level but also amplified, as most target regions are located near genes encoding transcription factors.ConclusionsWe suggest that stochasticity in the histone deacetylation pathway participates in the generation of genetic-independent behavioral inter-individual variability.

YY1 Upregulates Checkpoint Receptors and Downregulates Type I Cytokines in Exhausted, Chronically Stimulated Human T Cells

SummaryT cells infiltrate affected organs in chronic infections and malignancy, but they may fail to eradicate virus-infected cells or tumor because of exhaustion. This report describes a Yin Yang-1 (YY1)-centered mechanism for diverse components that have been correlated with exhaustion. Utilizing an in vitro reconstruction of chronic T cell activation, YY1 is shown to positively regulate the checkpoint receptors PD1, Lag3, and Tim3 and to negatively regulate the type I cytokines interleukin-2 (IL-2) (in collaboration with Ezh2 histone methyltransferase) and interferon gamma (IFN-γ). Other tests suggest that IL-2 failure drives a large component of cytotoxic functional decline rather than solely checkpoint receptor-ligand interactions that have been the focus of current anti-exhaustion therapies. Clinical evaluations confirm elevated YY1 and Ezh2 in melanoma tumor-infiltrating lymphocytes and in PD1+ T cells in patients with HIV. Exhaustion is revealed to be an active process as the culmination of repetitive two-signal stimulation in a feedback loop via CD3/CD28→p38MAPK/JNK→YY1→ exhaustion.

MiR-192-5p suppresses the growth of bladder cancer cells via targeting Yin Yang 1.

Bladder cancer has been identified as one of the most malignant cancers with high incidence and mortality. The underlying mechanisms by which regulate the tumorigenesis of bladder cancer deserve further investigation. Here, we found that miR-192-5p was downregulated in human bladder cancer cell lines and tissues. Overexpression of miR-192-5p significantly inhibited the growth of bladder cancer cells, while depletion of miR-192-5p exerted opposite effect. Bioinformatics analysis and molecular mechanism study identified that miR-192-5p targeted the transcription factor Yin Yang 1 (YY1) and decreased the expression level of YY1. Highly expressed YY1 attenuated the potential tumor suppressive function of miR-192-5p. The expression of miR-192-5p was negatively correlated with that of YY1 in bladder cancer tissues. These results indicated that miR-192-5p might serve as a promising target in bladder cancer diagnosis and therapy.

YinYang1 deficiency ameliorates joint inflammation in a murine model of rheumatoid arthritis by modulating Th17 cell activation

Yin Yang 1 (YY1) is a ubiquitously expressed transcription factor that functions in cooperation with various cofactors to regulate gene expression. In the immune system, YY1 enhances cytokine production and T helper (Th) 2 effector cell differentiation, resulting in the activation of inflammation. However, no studies have reported the role of YY1 in Th17 cell regulation, which is implicated in rheumatoid arthritis (RA). We investigated the expression of YY1 in Th17 cells in vitro and revealed increased levels of YY1 mRNA and protein. To elucidate the function of YY1 pathogenesis in RA, we used a collagen-induced arthritis (CIA) mouse model with YY1 deficiency. Deficiency of YY1 reduced the severity of arthritis and joint destruction. Moreover, Th17 cells were dramatically reduced in YY1-deficient mice. The cytokine interleukin (IL)-17 was decreased in YY1-deficient CD4+ T cells ex vivo and in vivo. Interestingly, the level of signal transducer and activator of transcription 3 (STAT3), tumor necrosis factor-α, IL-17, IL-6, and IL-1β were markedly decreased in YY1-deficient mice with CIA. The cytokine-inducing function of YY1 was more specific to IL-17 than to interferon-γ. YY1 plays a role in Th17 cell differentiation and RA pathogenesis. Our findings suggest that future RA therapies should target the regulatory mechanism involved in Th17 cell differentiation, in which YY1 may cooperate with the STAT3 signaling pathway.

Transcription factor YY1 is essential for iNKT cell development

Invariant natural killer T (iNKT) cells develop from CD4+CD8+ double-positive (DP) thymocytes and express an invariant Vα14-Jα18 T-cell receptor (TCR) α-chain. Generation of these cells requires the prolonged survival of DP thymocytes to allow for Vα14-Jα18 gene rearrangements and strong TCR signaling to induce the expression of the iNKT lineage-specific transcription factor PLZF. Here, we report that the transcription factor Yin Yang 1 (YY1) is essential for iNKT cell formation. Thymocytes lacking YY1 displayed a block in iNKT cell development at the earliest progenitor stage. YY1-deficient thymocytes underwent normal Vα14-Jα18 gene rearrangements, but exhibited impaired cell survival. Deletion of the apoptotic protein BIM failed to rescue the defect in iNKT cell generation. Chromatin immunoprecipitation and deep-sequencing experiments demonstrated that YY1 directly binds and activates the promoter of the Plzf gene. Thus, YY1 plays essential roles in iNKT cell development by coordinately regulating cell survival and PLZF expression.