Cutting Edge: Polycomb Repressive Complex 1 Subunit Cbx4 Positively Regulates Effector Responses in CD8 T Cells.

CTL differentiation is controlled by the crosstalk of various transcription factors and epigenetic modulators. Uncovering this process is fundamental to improving immunotherapy and designing novel therapeutic approaches. In this study, we show that polycomb repressive complex 1 subunit chromobox (Cbx)4 favors effector CTL differentiation in a murine model. Cbx4 deficiency in CTLs induced a transcriptional signature of memory cells and increased the memory CTL population during acute viral infection. It has previously been shown that besides binding to H3K27me3 through its chromodomain, Cbx4 functions as a small ubiquitin-like modifier (SUMO) E3 ligase in a SUMO-interacting motifs (SIM)-dependent way. Overexpression of Cbx4 mutants in distinct domains showed that this protein regulates CTL differentiation primarily in an SIM-dependent way and partially through its chromodomain. Our data suggest a novel role of a polycomb group protein Cbx4 controlling CTL differentiation and indicated SUMOylation as a key molecular mechanism connected to chromatin modification in this process.

Molecular basis of polycomb group protein-mediated fetal hemoglobin repression.

The switch from fetal hemoglobin (HbF) to adult hemoglobin (HbA) is a paradigm for developmental gene expression control with relevance to sickle cell disease and ß-thalassemia. Polycomb repressive complex (PRC) proteins regulate this switch, and an inhibitor of PRC2 has entered a clinical trial for HbF activation. Yet, how PRC complexes function in this process, their target genes, and relevant subunit composition are unknown. Here, we identified the PRC1 subunit BMI1 as a novel HbF repressor. We uncovered the RNA binding proteins LIN28B, IGF2BP1, and IGF2BP3 genes as direct BMI1 targets, and demonstrate that they account for the entirety of BMI1's effect on HbF regulation. BMI1 functions as part of the canonical PRC1 (cPRC1) subcomplex as revealed by the physical and functional dissection of BMI1 protein partners. Lastly, we demonstrate that BMI1/cPRC1 acts in concert with PRC2 to repress HbF through the same target genes. Our study illuminates how PRC silences HbF, highlighting an epigenetic mechanism involved in hemoglobin switching.

MiR-507 inhibits the progression of gastric carcinoma via targeting CBX4-mediated activation of Wnt/ß-catenin and HIF-1α pathways.

PURPOSE: Gastric carcinoma (GC) is a common malignant disease with high morbidity and mortality. MiR-507 has been confirmed as a tumor inhibitor which can suppress the progression of multiple cancers while its role in GC remains unknown. METHODS: In this study, the expression levels of miR-507 in the GC tissues and cells were observed by qRT-PCR, and CCK-8 assay, transwell asssay and TUNEL assay were used to observe the function of miR-507 on GC. The miRNA database and dual-luciferase reporter assay were used to investigate the downstream target of miR-507. Moreover, the activities of Wnt/ß-catenin and HIF-1α pathways were observed by western blot. RESULTS: The results showed that miR-507 was significantly downregulated in GC tissues and cell lines, and miR-507 upregulation effectively inhibited the proliferation and invasion and induced the apoptosis of GC cells. CBX4 was a downstream target of miR-507, and CBX4 could reverse the effects of miR-507 on the GC cells. Moreover, it was determined that miR-507 could inhibit CBX4 expression to suppress the activation of Wnt/ß-catenin and HIF-1α pathways. CONCLUSIONS: In conclusion, it suggests that miR-507 could inhibit the progression of GC via regulating CBX4-mediated activation of Wnt/ß-catenin and HIF-1α pathways.

Epigenetic regulation of T cells by Polycomb group proteins.

T cells are critical for pathogen elimination, tumor surveillance, and immunoregulation. The development, activation, and differentiation of CD8 and CD4 T lymphocytes are a set of complex and dynamically regulated events that require epigenetic control. The Polycomb group (PcG) proteins are a family of diverse and evolutionarily conserved epigenetic modulators fundamentally involved in several mechanisms of gene regulation. PcG proteins can assemble into distinct repressor complexes, the two most understood being the Polycomb Repressor Complex (PRC)1 and PRC2, which control chromatin structure mainly through posttranslational modifications of histones. In this review, we will summarize the most recent findings regarding the diverse roles performed by PcG proteins in T cell biology. We will focus on PRC1 and PRC2 contribution to the regulation of T cell development in the thymus, CD4 T cell differentiation in helper or regulatory phenotypes and CD8 T cell fate commitment in the context of infections and cancer, highlighting the known mechanisms and knowledge gaps that still need to be addressed.

Utility of BMI-1 and NANOG expression levels in survival prediction of pediatric acute lymphoblastic leukemia

ABSTRACT Background Acute lymphoblastic leukemia (ALL) is the most common malignancy in children characterized by the overproduction and accumulation of immature lymphoid cells in the bone marrow and peripheral blood. The BMI-1 is an important component of the Polycomb Repressive Complex-1 (PRC1). It is an important molecule for the self-renewal of hematopoietic stem cells (HSCs). The BMI-1 expression is generally high in HSCs and decreases after cell differentiation. The BMI-1 is required for the maintenance of normal and cancer stem cells and has been reported as an oncogene in various tumors. The NANOG is a homeodomain transcription factor responsible for maintaining the stem cell compartment at the blastocyst stage of developing embryos. The NANOG gene has been proven to be transcribed in CD34+ cells and different leukemic cells. Methods The ribonucleic acid (RNA) was extracted from the peripheral blood mononuclear cells (PBMNCs) of 30 pediatric ALL patients (16 B-ALL and 14 T-ALL) and 14 healthy controls. The Bmi-1 and NANOG expression levels were determined using the quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). Results Compared to normal controls, patients with ALL exhibited upregulated levels of Bmi-1 (p = 0.03). Patients who overexpressed Bmi-1 and NANOG displayed a significantly worse survival than low-expressing patients (hazard ratio (HR) 5.74, 95% confidence interval (CI):1.48-22, p = 0.012 and HR 3.8, 95% CI:1.009-14.3, p = 0.048, respectively). Conclusions Taken together, these data suggest that the Bmi-1 and NANOG might serve as a novel survival predictor in ALL patients. Our observation also suggests that the Bmi-1 and NANOG could serve as new therapeutic targets for treatment of pediatric ALL.

CURLY LEAF Regulates MicroRNA Activity by Controlling ARGONAUTE 1 Degradation in Plants.

CURLY LEAF (CLF) encodes the methyltransferase subunit of the Polycomb Repressor Complex 2 (PRC2), which regulates the expression of target genes through H3K27 trimethylation. We isolated a new CLF mutant allele (clf-78) using a genetic screen designed to identify microRNA (miRNA) deficient mutants. CLF mutant plants showed impaired miRNA activity caused by increased ubiquitination and enhanced degradation of ARGONAUTE 1 (AGO1) in specific tissues. Such CLF-mediated AGO1 regulation was evident when plants were exposed to UV radiation, which caused increased susceptibility of clf mutants to some UV-induced responses. Furthermore, we showed that CLF directly regulates FBW2, which in turn triggers AGO1 degradation in the clf mutants. Interestingly, AGO1 bound to a target appeared particularly prone to degradation in the mutant plants, a process that was exacerbated when the complex bound a non-cleavable target. Thus, prolonged AGO1-target interaction seems to favor AGO1 degradation, suggesting that non-cleavable miRNA targets may overcome translation inhibition by modulating AGO1 stability in plants.

The impact of Polycomb group (PcG) and Trithorax group (TrxG) epigenetic factors in plant plasticity.

Current advances indicate that epigenetic mechanisms play important roles in the regulatory networks involved in plant developmental responses to environmental conditions. Hence, understanding the role of such components becomes crucial to understanding the mechanisms underlying the plasticity and variability of plant traits, and thus the ecology and evolution of plant development. We now know that important components of phenotypic variation may result from heritable and reversible epigenetic mechanisms without genetic alterations. The epigenetic factors Polycomb group (PcG) and Trithorax group (TrxG) are involved in developmental processes that respond to environmental signals, playing important roles in plant plasticity. In this review, we discuss current knowledge of TrxG and PcG functions in different developmental processes in response to internal and environmental cues and we also integrate the emerging evidence concerning their function in plant plasticity. Many such plastic responses rely on meristematic cell behavior, including stem cell niche maintenance, cellular reprogramming, flowering and dormancy as well as stress memory. This information will help to determine how to integrate the role of epigenetic regulation into models of gene regulatory networks, which have mostly included transcriptional interactions underlying various aspects of plant development and its plastic response to environmental conditions.

DNA damage-induced heterogeneous nuclear ribonucleoprotein K sumoylation regulates p53 transcriptional activation.

Heterogeneous nuclear ribonucleoprotein (hnRNP) K is a nucleocytoplasmic shuttling protein that is a key player in the p53-triggered DNA damage response, acting as a cofactor for p53 in response to DNA damage. hnRNP K is a substrate of the ubiquitin E3 ligase MDM2 and, upon DNA damage, is de-ubiquitylated. In sharp contrast with the role and consequences of the other post-translational modifications, nothing is known about the role of SUMO conjugation to hnRNP K in p53 transcriptional co-activation. In the present work, we show that hnRNP K is modified by SUMO in lysine 422 within its KH3 domain, and sumoylation is regulated by the E3 ligase Pc2/CBX4. Most interestingly, DNA damage stimulates hnRNP K sumoylation through Pc2 E3 activity, and this modification is required for p53 transcriptional activation. Abrogation of hnRNP K sumoylation leads to an aberrant regulation of the p53 target gene p21. Our findings link the DNA damage-induced Pc2 activation to the p53 transcriptional co-activation through hnRNP K sumoylation.

Polycomb group gene function in sexual and asexual seed development in angiosperms.

In sexually reproducing angiosperms, double fertilization initiates seed development, giving rise to two fertilization products, the embryo and the endosperm. In the endosperm, a terminal nutritive tissue that supports embryo growth, certain genes are expressed differentially depending on their parental origin, and this genomic imbalance is required for proper seed formation. This parent-of-origin effect on gene expression, called genomic imprinting, is controlled epigenetically through histone modifications and DNA methylation. In the sexual model plant Arabidopsis, the Polycomb group (PcG) genes of the plant Fertilization Independent Seed (FIS)-class control genomic imprinting by specifically silencing maternal or paternal target alleles through histone modifications. Mutations in FIS genes can lead to a bypass in the requirement of fertilization for the initiation of endosperm development and seed abortion. In this review, we discuss the role of the FIS complex in establishing and maintaining genomic imprinting, focusing on recent advances in elucidating the expression and function of FIS-related genes in maize, rice, and Hieracium, and particularly including apomictic Hieracium species that do not require paternal contribution and thus form seeds asexually. Surprisingly, not all FIS-mediated functions described in Arabidopsis are conserved. However, the function of some PcG components are required for viable seed formation in seeds formed via sexual and asexual processes (apomixis) in Hieracium, suggesting a conservation of the seed viability function in some eudicots.

Implication of abnormal epigenetic patterns for human diseases.

Significant evidences have brought new insights on the mechanisms by which epigenetic machinery proteins regulate gene expression, leading to a redefinition of chromatin regulation in terms of modification of core histones, DNA methylation, RNA-mediated silencing pathways, action of methylation-dependent sensitive insulators and Polycomb/Trithorax group proteins. Consistent with these fundamental aspects, an increasing number of human pathologies have been found to be associated with aberrant epigenetics regulation, including cancer, mental retardation, neurodegenerative symptoms, imprinting disorders, syndromes involving chromosomal instabilities and a great number of human life-threatening diseases. The possibility of reversing epigenetic marks, in contrast to genetic code, may provide new pharmacological targets for emerging therapeutic intervention.