YY1 Binding Sites Research Articles

The L27 domain of MPP7 enhances TAZ-YY1 cooperation to renew muscle stem cells.

Stem cells regenerate differentiated cells to maintain and repair tissues and organs. They also replenish themselves, i.e. self-renew, to support a lifetime of regenerative capacity. Here we study the renewal of skeletal muscle stem cell (MuSC) during regeneration. The transcriptional co-factors TAZ/YAP (via the TEAD transcription factors) regulate cell cycle and growth while the transcription factor YY1 regulates metabolic programs for MuSC activation. We show that MPP7 and AMOT join TAZ and YY1 to regulate a selected number of common genes that harbor TEAD and YY1 binding sites. Among these common genes, Carm1 can direct MuSC renewal. We demonstrate that the L27 domain of MPP7 enhances the interaction as well as the transcriptional activity of TAZ and YY1, while AMOT acts as an intermediate to bridge them together. Furthermore, MPP7, TAZ and YY1 co-occupy the promoters of Carm1 and other common downstream genes. Our results define a renewal program comprised of two progenitor transcriptional programs, in which selected key genes are regulated by protein-protein interactions, dependent on promoter context.

Prediction of YY1 loop anchor based on multi-omics features

The three-dimensional structure of chromatin is crucial for the regulation of gene expression. YY1 promotes enhancer-promoter interactions in a manner analogous to CTCF-mediated chromatin interactions. However, little is known about which YY1 binding sites can form loop anchors. In this study, the LightGBM model was used to predict YY1-loop anchors by integrating multi-omics data. Due to the large imbalance in the number of positive and negative samples, we use AUPRC to reflect the quality of the classifier. The results show that the LightGBM model exhibits strong predictive performance (AUPRC≥0.93). To verify the robustness of the model, the dataset was divided into training and testing sets at a 4:1 ratio. The results show that the model performs well for YY1-loop anchor prediction on both the training and independent testing sets. Additionally, we ranked the importance of the features and found that the formation of YY1-loop anchors is primarily influenced by the co-binding of transcription factors CTCF, SMC3, and RAD21, as well as histone modifications and sequence context.

YY1 is a transcriptional activator of the mouse LINE-1 Tf subfamily.

Long interspersed element type 1 (LINE-1, L1) is an active autonomous transposable element in human and mouse genomes. L1 transcription is controlled by an internal RNA polymerase II promoter in the 5' untranslated region (5'UTR) of a full-length L1. It has been shown that transcription factor YY1 binds to a conserved sequence at the 5' end of the human L1 5'UTR and primarily dictates where transcription initiates. Putative YY1-binding motifs have been predicted in the 5'UTRs of two distinct mouse L1 subfamilies, Tf and Gf. Using site-directed mutagenesis, in vitro binding and gene knockdown assays, we experimentally tested the role of YY1 in mouse L1 transcription. Our results indicate that Tf, but not Gf subfamily, harbors functional YY1-binding sites in 5'UTR monomers and YY1 functions as a transcriptional activator for the mouse Tf subfamily. Activation of Tf transcription by YY1 during early embryogenesis is also supported by a reanalysis of published zygotic knockdown data. Furthermore, YY1-binding motifs are solely responsible for the synergistic interaction between Tf monomers, consistent with a model wherein distant monomers act as enhancers for mouse L1 transcription. The abundance of YY1-binding sites in Tf elements also raise important implications for gene regulation across the genome.

Identification and Functional Analysis of E3 Ubiquitin Ligase g2e3 in Chinese Tongue Sole, Cynoglossus semilaevis.

Gametogenesis, the intricate developmental process responsible for the generation of germ cells (gametes), serves as a fundamental prerequisite for the perpetuation of the reproductive cycle across diverse organisms. The g2e3 enzyme is a putative ubiquitin E3 ligase implicated in the intricate regulatory mechanisms underlying cellular proliferation and division processes. The present study delves into the function of G2/M phase-specific E3 ubiquitin protein ligase (Cs-g2e3) in gametogenesis in Chinese Tongue Sole (Cynoglossus semilaevis). Sequence analysis shows that the Cs-g2e3 mRNA spans 6479 bp, encoding a 733 amino acid protein characterized by three conserved structural domains: PHD, RING, and HECT-typical of HECT E3 ubiquitin ligases. The predominant expression of Cs-g2e3 in the gonad tissues is further verified by qPCR. The expression profile of Cs-g2e3 in the gonads of the Chinese Tongue Sole is analyzed at different ages, and the results show that its expression peaks at 8 months of age and then begins to decline and stabilize. It is noteworthy that the expression level remains significantly elevated compared to that observed during the juvenile period. In situ hybridization shows that the mRNA of Cs-g2e3 is mainly localized in the germ cells of the ovary and the testis. RNA interference experiments show that the knockdown of Cs-g2e3 in ovarian and testicular germ cell lines significantly downregulates the expression of key genes involved in oogenesis (e.g., sox9 and cyp19a) and spermatogenesis (e.g., tesk1 and piwil2), respectively. Furthermore, the analysis of mutations in the transcription factor binding sites reveals that mutations within the Myogenin, YY1, and JunB binding sites significantly impact the transcriptional activity of the Cs-g2e3 gene, with the mutation in the YY1 binding site exhibiting the most pronounced effect (p < 0.001). This study contributes to a deeper understanding of the tissue-specific expression patterns of Cs-g2e3 across various tissues in Cynoglossus semilaevis, as well as the potential regulatory influences of transcription factors on its promoter activity. These findings may facilitate future research endeavors aimed at elucidating the expression and functional roles of the Cs-g2e3 gene.

Abstract B012: Transcriptional activation of mouse LINE-1 promoter by transcription factor YY1

Abstract Long interspersed element type 1 (LINE-1) are highly abundant non-LTR retrotransposons in mammalian genomes. LINE-1 hypomethylation and overexpression has been considered as a hallmark of many human cancers. Moreover, active movement of LINE-1 results in insertional mutagenesis and may contribute to cancer initiation or progression. Transcription is the initial and critical regulatory step for active LINE-1 movement. Therefore, investigating LINE-1 transcriptional regulation is important for our understanding of LINE-1’s role in cancer. In human LINE-1, an intact YY1 transcription factor binding motif is required for accurate transcription initiation. Two subfamilies of mouse LINE-1, Tf_I and Gf_I, have predicted YY1 binding motifs in their promoter region but their role in mouse LINE-1 transcription has not been characterized. In this study, we aim to investigate the role of these putative YY1 motifs in Tf_I and Gf_I subfamilies. Promoter sequences carrying the wild-type or mutant YY1 motifs were cloned into a dual-luciferase reporter system. Reporter assays showed transcription inactivation upon mutation of the YY1 motif for the Tf_I subfamily. The electrophoretic mobility shift assay (EMSA) demonstrated specific interaction of the Tf_I promoter sequence with the YY1 protein. Knockdown of YY1 protein level in cells reduced Tf_I promoter activity by 2-fold compared to the wild-type control. These results indicate that YY1 is a transcriptional activator of mouse LINE-1 Tf_I subfamily. On the other hand, our data suggest that the predicted YY1 binding site in the promoter of Gf_I subfamily is not functional due to one nucleotide deviation from the consensus YY1 motif. Indeed, restoring it to the conserved YY1 motif sequence enhanced the promoter activity by 6-fold. In EMSA, YY1 protein did not interact with the putative YY1 motif of the Gf_I subfamily but did so when the motif was restored to consensus YY1 sequence. Findings from our study increase our understanding of the transcriptional regulation of different mouse LINE-1 subfamilies, highlight the differing roles of YY1 in regulating human and mouse L1 transcription, and have important implications in the role of LINE-1s during cancer development. Citation Format: Karani Saha, Grace Nielsen, Wenfeng An. Transcriptional activation of mouse LINE-1 promoter by transcription factor YY1 [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr B012.

BRD4-binding enhancer promotes CRC progression by interacting with YY1 to activate the Wnt pathway through upregulation of TCF7L2

Colorectal carcinoma (CRC), one of the most life-threatening cancer types, is associated with aberrant expression of epigenetic modifiers and activation of the Wnt pathway. However, the role of epigenetic regulators in driving cancer cell proliferation and their potential as therapeutic targets affecting the Wnt pathway remain unclear. In this study, BRD4 was found to promote the progression of CRC both in vitro and in vivo. The expression of BRD4 correlated with shortened CRC patient survival. In addition, BRD4 function was strongly correlated with the Wnt pathway, but rather through regulation of TCF7L2 at transcriptional levels. BRD4 and H3K27ac have overlapping occupancies in the cis-regulatory elements of TCF7L2, suggesting enhancer-based epigenetic regulation. Numerous YY1 binding sites were found in the abovementioned region. YY1 recruited BRD4 to bind to cis-regulatory elements of TCF7L2, thereby regulating the expression of TCF7L2. Altogether, this study validates that BRD4 performs a canonical epigenetic regulatory function in CRC and can be used in the treatment of Wnt pathway-dependent CRC or other malignancies with clinically available bromodomain inhibitors.

YY1 Binding to Regulatory Elements That Lack Enhancer Activity Promotes Locus Folding and Gene Activation

Enhancers activate their cognate promoters over huge distances but how enhancer/promoter interactions become established is not completely understood. There is strong evidence that cohesin-mediated loop extrusion is involved but this does not appear to be a universal mechanism. Here, we identify an element within the mouse immunoglobulin lambda (Igλ) light chain locus, HSCλ1, that has characteristics of active regulatory elements but lacks intrinsic enhancer or promoter activity. Remarkably, knock-out of the YY1 binding site from HSCλ1 reduces Igλ transcription significantly and disrupts enhancer/promoter interactions, even though these elements are >10 kb from HSCλ1. Genome-wide analyses of mouse embryonic stem cells identified 2671 similar YY1-bound, putative genome organizing elements that lie within CTCF/cohesin loop boundaries but that lack intrinsic enhancer activity. We suggest that such elements play a fundamental role in locus folding and in facilitating enhancer/promoter interactions.

Dynamic nucleosome remodeling mediated by YY1 underlies early mouse development.

Nucleosome positioning can alter the accessibility of DNA-binding proteins to their cognate DNA elements, and thus its precise control is essential for cell identity and function. Mammalian preimplantation embryos undergo temporal changes in gene expression and cell potency, suggesting the involvement of dynamic epigenetic control during this developmental phase. However, the dynamics of nucleosome organization during early development are poorly understood. In this study, using a low-input MNase-seq method, we show that nucleosome positioning is globally obscure in zygotes but becomes well defined during subsequent development. Down-regulation of the chromatin assembly in embryonic stem cells can partially reverse nucleosome organization into a zygote-like pattern, suggesting a possible link between the chromatin assembly pathway and fuzzy nucleosomes in zygotes. We also reveal that YY1, a zinc finger-containing transcription factor expressed upon zygotic genome activation, regulates the de novo formation of well-positioned nucleosome arrays at the regulatory elements through identifying YY1-binding sites in eight-cell embryos. The YY1-binding regions acquire H3K27ac enrichment around the eight-cell and morula stages, and YY1 depletion impairs the morula-to-blastocyst transition. Thus, our study delineates the remodeling of nucleosome organization and its underlying mechanism during early mouse development.

Functional Genomics Analysis to Disentangle the Role of Genetic Variants in Major Depression.

Understanding the molecular basis of major depression is critical for identifying new potential biomarkers and drug targets to alleviate its burden on society. Leveraging available GWAS data and functional genomic tools to assess regulatory variation could help explain the role of major depression-associated genetic variants in disease pathogenesis. We have conducted a fine-mapping analysis of genetic variants associated with major depression and applied a pipeline focused on gene expression regulation by using two complementary approaches: cis-eQTL colocalization analysis and alteration of transcription factor binding sites. The fine-mapping process uncovered putative causally associated variants whose proximal genes were linked with major depression pathophysiology. Four colocalizing genetic variants altered the expression of five genes, highlighting the role of SLC12A5 in neuronal chlorine homeostasis and MYRF in nervous system myelination and oligodendrocyte differentiation. The transcription factor binding analysis revealed the potential role of rs62259947 in modulating P4HTM expression by altering the YY1 binding site, altogether regulating hypoxia response. Overall, our pipeline could prioritize putative causal genetic variants in major depression. More importantly, it can be applied when only index genetic variants are available. Finally, the presented approach enabled the proposal of mechanistic hypotheses of these genetic variants and their role in disease pathogenesis.

Transcriptional Regulation of Yin-Yang 1 Expression through the Hypoxia Inducible Factor-1 in Pediatric Acute Lymphoblastic Leukemia.

Yin-Yang transcription factor 1 (YY1) is involved in tumor progression, metastasis and has been shown to be elevated in different cancers, including leukemia. The regulatory mechanism underlying YY1 expression in leukemia is still not understood. Bioinformatics analysis reveal three Hypoxia-inducible factor 1-alpha (HIF-1α) putative binding sites in the YY1 promoter region. The regulation of YY1 by HIF-1α in leukemia was analyzed. Mutation of the putative YY1 binding sites in a reporter system containing the HIF-1α promoter region and CHIP analysis confirmed that these sites are important for YY1 regulation. Leukemia cell lines showed that both proteins HIF-1α and YY1 are co-expressed under hypoxia. In addition, the expression of mRNA of YY1 was increased after 3 h of hypoxia conditions and affect several target genes expression. In contrast, chemical inhibition of HIF-1α induces downregulation of YY1 and sensitizes cells to chemotherapeutic drugs. The clinical implications of HIF-1α in the regulation of YY1 were investigated by evaluation of expression of HIF-1α and YY1 in 108 peripheral blood samples and by RT-PCR in 46 bone marrow samples of patients with pediatric acute lymphoblastic leukemia (ALL). We found that the expression of HIF-1α positively correlates with YY1 expression in those patients. This is consistent with bioinformatic analyses of several databases. Our findings demonstrate for the first time that YY1 can be transcriptionally regulated by HIF-1α, and a correlation between HIF-1α expression and YY1 was found in ALL clinical samples. Hence, HIF-1α and YY1 may be possible therapeutic target and/or biomarkers of ALL.

Genetic Diversity of HPV 16 and HPV 18 Based on Partial Long Control Region in Iranian Women.

Background Human papillomavirus (HPV) 16 and HPV 18 account for 75% of all cervical cancers. The L1 gene, encoding the major surface protein (MSP), is used to classify HPV types (lineages and sublineages), genotypes, and intratypic variants. Therefore, this study aimed to investigate the lineages, sublineages, genetic variabilities, and mutation effects on transcription factor binding sites by using partial sequences of the HPV 16 and HPV 18 long control regions (LCRs) in these samples. Materials and Methods After DNA isolation from 56 positive samples, the LCR of HPV 16 and HPV 18 were amplified using specific primers, and phylogenetic trees were drawn through MEGA X. Compared to the reference sequences, single nucleotide polymorphisms (SNPs) were identified. The transcription binding sites were also evaluated using the online PROMO database. Results The LCRs of 52 samples were successfully sequenced. Overall, 81.58% of all HPV 16 variants belonged to the D1 sublineage, followed by A4 (13.16%), A1 (2.63%), and C1 (2.63%) sublineages. All HPV 18 isolates belonged to A sublineage, 92.85% to A3 sublineage, and 7.15% to A4 sublineage. Out of 27 SNPs in the HPV 16 LCR, A7382T, T7384G, C7387T, C7393G, A7431G, T7448C, and C7783A were HPV 16-specific. Also, among 14 SNPs in the HPV 18 LCR, C7577A and A7943T were not previously reported. An insertion (C) between 7432 and 7433 positions was identified in all studied HPV 16 variants. Besides, most of the HPV 16 mutations were embedded in the YY1, TFIID, Oct-2, and NF-1 binding sites, while c-Fos and MBF1, as the most common binding sites, were affected by HPV 18 LCR mutations. Conclusion The present results showed that D1 and A3 were the dominant sublineages of HPV 16 and HPV 18, respectively. Therefore, women infected with these variants need to be examined in further longitudinal studies to obtain more information about the oncogenic potential of these dominant variants in Iran. Besides, YY1, TFIID, Oct-2, NF-1, c-Fos, and MBF1 were the most frequent binding sites, which were influenced by the mutations.

Splicing Factor SRSF1 Promotes Tumorigenesis Via Oncogenic Splice-Switching and Predicts Poor Prognosis in Multiple Myeloma

ObjectiveDysregulation of alternative splicing (AS) triggers many tumors, yet its contribution to multiple myeloma (MM) has not been elucidated. Our study aims to reveal the role of AS in MM progression, and to explore the molecular mechanisms of the candidate splicing factor (SF), thus valuates its feasibility as a treatment target and prognostic factor.Design and results 1.Gene set enrichment analysis (GSEA) revealed a significant difference in the expression pattern of the alternative splicing pathway genes, notably enriched in MM patients (Figure 1A). And, the splicing factor SRFS1 expression showed concordant differential expression in MM versus normal donors in two datasets (GSE6477, GSE13591). Kaplan-Meier analysis showed that high SRSF1 expression in CD138 + MM cells was associated with decreased PFS and poor OS (GSE9782) (Figure 1B). Moreover, the SRSF1 levels appeared a progressive increase in the progression of plasma cell dyscrasias (MGUS, SMM, MM and PCL) (Figure 1C). A cohort of 57 newly diagnosed MM patients was uniformly treated and followed. Univariate and multivariate analyses indicated that high SRSF1 expression was correlated with decreased PFS and OS. The c-indices of the Cox model fit with the combination of RISS and SRSF1 were higher than those of models fit without SRSF1, suggesting that SRSF1 improved the prognostic stratification of patients with MM.2.In vitro, SRSF1 downregulation in MM cells resulted in decreased proliferation, increased apoptosis and cell cycle arrest in G1 phase. In orthotopic MM xenograft models, bioluminescent imaging monitoring revealed a decreased burden of disease and a prolongation in overall survival in mice injected with SRSF1-shRNA cells versus the control (Figure 1D-F).3.Pearson correlation analysis suggested that the expression of TF YY1 was positively correlated with SRSF1 in five sets of GEO (Figure 1G). CHIP-seq BigWig files were downloaded from GSE31477 and Integrative Genomics Viewer (IGV) tracks displayed the binding site of YY1 at SRSF1 promoter locus from chr17: 56084421 to 56084751 (Figure 1H). CHIP-qPCR assay confirmed that endogenous YY1 directly interacted with the core element of the SRSF1 promoter in myeloma cells. Silencing of YY1 expression decreased the luciferase activity of the reporter construct carrying wild-type SRSF1 promoter region but not mutant in the YY1 binding site. Consistent with the effects of SRSF1, downregulation YY1 displayed anticancer activity in myeloma cells. Kaplan-Meier analysis showed that high YY1 expression in CD138 + myeloma cells was associated with decreased PFS and poor OS.4.RNA-seq analysis revealed a total of 7678 SRSF1-regulated AS events in LP-1 cell with an FDR cut-off of <0.05. Among them, the index of percent spliced in percentage-spliced-in (PSI) was upregulated in 4098 AS events and downregulated in 3580 AS via the downregulation of SRSF1. Changes in alternative splicing events were analyzed by replicate multivariate analysis of transcript splicing (rMATS) to identify downstream key genes regulated by SRSF1. Various types of AS events, including skipped exons (SEs), alternative 5‘ ss exons (A5SSs), alternative 3‘ ss exons (A3SSs), retained introns (RIs), and mutually exclusive exons (MXEs), can be regulated by SRSF1, and of these, SE is the most common type of SRSF1-regulated AS events (Figure 1I-O). The KEGG Pathway and GO analysis revealed that SRSF1-regulated AS events were involved in spliceosome, cell cycle and cellular process. Among the most significant AS events, we noted RBBP6, which isoforms have been reported to exhibit opposite effect on oncogenic activity.5.RNA-seq and subsequent validation indicated that SRSF1 knockdown caused a significantly decreased iso1 and increased iso3 of RBBP6. An opposite effect on myeloma proliferation between iso1 and iso3 was observed upon overexpression of individual proteins. Moreover, the level of RBBP6 iso1 is associated with poor prognosis, whereas iso3 expression is associated with favorable prognosis in MM patientsConclusionOur study uncovered that SRSF1-regulated aberrant AS facilitated myeloma progression through creating reducing normal isoforms and increasing oncogenic isoforms (Figure 1P). Moreover, SRSF1 and its critical splicing target could act as an independent prognostic factor for MM patients. Thus, SRSF1 might be considered as a valuable therapeutic target and a potential prognostic biomarker for MM. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Growth hormone promotes hepatic gluconeogenesis by enhancing BTG2\u2013YY1 signaling pathway

Growth hormone (GH) is one of the critical factors in maintaining glucose metabolism. B-cell translocation gene 2 (BTG2) and yin yang 1 (YY1) are key regulators of diverse metabolic processes. In this study, we investigated the link between GH and BTG2–YY1 signaling pathway in glucose metabolism. GH treatment elevated the expression of hepatic Btg2 and Yy1 in primary mouse hepatocytes and mouse livers. Glucose production in primary mouse hepatocytes and serum blood glucose levels were increased during GH exposure. Overexpression of hepatic Btg2 and Yy1 induced key gluconeogenic enzymes phosphoenolpyruvate carboxykinase 1 (PCK1) and glucose-6 phosphatase (G6PC) as well as glucose production in primary mouse hepatocytes, whereas this phenomenon was markedly diminished by knockdown of Btg2 and Yy1. Here, we identified the YY1-binding site on the Pck1 and G6pc gene promoters using reporter assays and point mutation analysis. The regulation of hepatic gluconeogenic genes induced by GH treatment was clearly linked with YY1 recruitment on gluconeogenic gene promoters. Overall, this study demonstrates that BTG2 and YY1 are novel regulators of GH-dependent regulation of hepatic gluconeogenic genes and glucose production. BTG2 and YY1 may be crucial therapeutic targets to intervene in metabolic dysfunction in response to the GH-dependent signaling pathway.

Transcriptional regulation of human DUSP4 gene by cancer-related transcription factors.

Dual specificity phosphatase 4 (DUSP4), a member of the dual specificity phosphatase family, is responsible for the dephosphorylation and inactivation of ERK, JNK and p38, which are mitogen-activated protein kinases involved in cell proliferation, differentiation and apoptosis, but also in inflammation processes. Given its importance for cellular signalling, DUSP4 is subjected to a tight regulation and there is growing evidence that its expression is dysregulated in several tumours. However, the mechanisms underlying DUSP4 transcriptional regulation remain poorly understood. Here, we analysed the regulation of the human DUSP4 promoters 1 and 2, located upstream of exons 1 and 2, respectively, by the cancer-related transcription factors (TFs) STAT3, FOXA1, CTCF and YY1. The presence of binding sites for these TFs was predicted in both promoters through the in silico analysis of DUSP4, and their functionality was assessed through luciferase activity assays. Regulatory activity of the TFs tested was found to be promoter-specific. While CTCF stimulated the activity of promoter 2 that controls the transcription of variants 2 and X1, STAT3 stimulated the activity of promoter 1 that controls the transcription of variant 1. YY1 positively regulated both promoters, although to different extents. Through site-directed mutagenesis, the functionality of YY1 binding sites present in promoter 2 was confirmed. This study provides novel insights into the transcriptional regulation of DUSP4, contributing to a better comprehension of the mechanisms of its dysregulation observed in several types of cancer.

TP73-AS1 is induced by YY1 during TMZ treatment and highly expressed in the aging brain.

Aging is a factor associated with poor prognosis in glioblastoma (GBM). It is therefore important to understand the molecular features of aging contributing to GBM morbidity. TP73-AS1 is a long noncoding RNA (lncRNA) over expressed in GBM tumors shown to promote resistance to the chemotherapeutic temozolomide (TMZ), and tumor aggressiveness. How the expression of TP73-AS1 is regulated is not known, nor is it known if its expression is associated with aging. By analyzing transcriptional data obtained from natural and pathological aging brain, we found that the expression of TP73-AS1 is high in pathological and naturally aging brains. YY1 physically associates with the promoter of TP73-AS1 and we found that along with TP73-AS1, YY1 is induced by TMZ. We found that the TP73-AS1 promoter is activated by TMZ, and by YY1 over expression. Using CRISPRi to deplete YY1, we found that YY1 promotes up regulation of TP73-AS1 and the activation of its promoter during TMZ treatment. In addition, we identified two putative YY1 binding sites within the TP73-AS1 promoter, and used mutagenesis to find that they are essential for TMZ mediated promoter activation. Together, our data positions YY1 as an important TP73-AS1 regulator, demonstrating that TP73-AS1 is expressed in the natural and pathological aging brain, including during neurodegeneration and cancer. Our findings advance our understanding of TP73-AS1 expression, bringing forth a new link between TMZ resistance and aging, both of which contribute to GBM morbidity.

YY1 interacts with guanine quadruplexes to regulate DNA looping and gene expression.

SummaryThe DNA guanine quadruplexes (G4) play important roles in multiple cellular processes, including DNA replication, transcription and maintenance of genome stability. Here, we showed that Yin Yang-1 (YY1) can bind directly to G4 structures. ChIP-Seq results revealed that YY1 binding sites overlap extensively with G4 structure loci in chromatin. We also observed that YY1’s dimerization and its binding with G4 structures contribute to YY1-mediated long-range DNA looping. Displacement of YY1 from G4 structure sites disrupts substantially the YY1-mediated DNA looping. Moreover, treatment with G4-stabilizing ligands modulates the expression of not only those genes with G4 structures in their promoters, but also those associated with distal G4 structures that are brought to close proximity via YY1-mediated DNA looping. Together, we identified YY1 as a novel DNA G4-binding protein, and revealed that YY1-mediated long-range DNA looping requires its dimerization and occurs, in part, through its recognition of G4 structure.

SNP rs17079281 decreases lung cancer risk through creating an YY1-binding site to suppress DCBLD1 expression

Genome-wide association studies (GWAS) have identified numerous genetic variants that are associated with lung cancer risk, but the biological mechanisms underlying these associations remain largely unknown. Here we investigated the functional relevance of a genetic region in 6q22.2 which was identified to be associated with lung cancer risk in our previous GWAS. We performed linkage disequilibrium (LD) analysis and bioinformatic prediction to screen functional SNPs linked to a tagSNP in 6q22.2 loci, followed by two case-control studies and a meta-analysis with 4403 cases and 5336 controls to identify if these functional SNPs were associated with lung cancer risk. A novel SNP rs17079281 in the DCBLD1 promoter was identified to be associated with lung cancer risk in Chinese populations. Compared with those with C allele, patients with T allele had lower risk of adenocarcinoma (adjusted OR = 0.86; 95% CI: 0.80–0.92), but not squamous cell carcinoma (adjusted OR = 0.99; 95% CI: 0.91–1.10), and patients with the C/T or T/T genotype had lower levels of DCBLD1 expression than those with C/C genotype in lung adenocarcinoma tissues. We performed functional assays to characterize its biological relevance. The results showed that the T allele of rs17079281 had higher binding affinity to transcription factor YY1 than the C allele, which suppressed DCBLD1 expression. DCBLD1 behaved like an oncogene, promoting tumor growth by influencing cell cycle progression. These findings suggest that the functional variant rs17079281C>T decreased lung adenocarcinoma risk by creating an YY1-binding site to suppress DCBLD1 expression, which may serve as a biomarker for assessing lung cancer susceptibility.

Template Activating Factor-I α Regulates Retroviral Silencing during Reprogramming

Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) is accompanied by dramatic changes in epigenetic programs, including silencing of endogenous and exogenous retroviruses. Here, we utilized replication-defective and persistent Sendai virus (SeVdp)-based vectors to monitor retroviral silencing during reprogramming. We observed that retroviral silencing occurred at an early reprogramming stage without a requirement for KLF4 or the YY1-binding site in the retroviral genome. Insertional chromatin immunoprecipitation (iChIP) enabled us to isolate factors assembled on the silenced provirus, including components of inhibitor of histone acetyltransferase (INHAT), which includes the SET/TAF-I oncoprotein. Knockdown of SET/TAF-I in mouse embryonic fibroblasts (MEFs) diminished retroviral silencing during reprogramming, and overexpression of template activating factor-I α (TAF-Iα), a SET/TAF-I isoform predominant in embryonic stem cells (ESCs), reinforced retroviral silencing by an SeVdp-based vector that is otherwise defective inretroviral silencing. Our results indicate an important role for TAF-Iα in retroviral silencing during reprogramming.

Evolution patterns of Peg3 and H19-ICR

Mammalian imprinted domains are regulated through small genomic regions termed Imprinting Control Regions (ICRs). In the current study, the evolution patterns of the ICRs of Peg3 and H19-imprinted domains were analyzed using the genomic sequences derived from a large number of mammals. The results indicated that multiple YY1 and CTCF binding sites are localized within the Peg3 and H19-ICR in all the mammals tested. The numbers of YY1 and CTCF binding sites are variable among individual species, yet positively correlate with the presence of tandem repeats within the Peg3 and H19-ICRs. Thus, multiple YY1 and CTCF binding sites within the respective ICRs may have been maintained through tandem repeats/duplications. The unit lengths of tandem repeats are also non-random and locus-specific, 140 and 400 bp for the Peg3 and H19-ICRs. Overall, both Peg3 and H19-ICRs may have co-evolved with two unique features, multiple transcription factor binding sites and tandem repeats.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature