Gene Summary

Gene:CTCF; CCCTC-binding factor
Aliases: MRD21
Summary:This gene is a member of the BORIS + CTCF gene family and encodes a transcriptional regulator protein with 11 highly conserved zinc finger (ZF) domains. This nuclear protein is able to use different combinations of the ZF domains to bind different DNA target sequences and proteins. Depending upon the context of the site, the protein can bind a histone acetyltransferase (HAT)-containing complex and function as a transcriptional activator or bind a histone deacetylase (HDAC)-containing complex and function as a transcriptional repressor. If the protein is bound to a transcriptional insulator element, it can block communication between enhancers and upstream promoters, thereby regulating imprinted expression. Mutations in this gene have been associated with invasive breast cancers, prostate cancers, and Wilms' tumors. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2010]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:transcriptional repressor CTCF
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (29)
Pathways:What pathways are this gene/protein implicaed in?
Show (1)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • RNA, Untranslated
  • Chromosome 16
  • p53 Protein
  • Binding Sites
  • RNA-Binding Proteins
  • Stomach Cancer
  • bcl-2-Associated X Protein
  • Histones
  • Neoplasm Proteins
  • CpG Islands
  • CCCTC-Binding Factor
  • Long Noncoding RNA
  • Chromatin
  • Testicular Cancer
  • IGF2
  • beta-Galactosidase
  • Gene Expression Profiling
  • Epigenetics
  • Protein Binding
  • Repressor Proteins
  • X Chromosome Inactivation
  • Base Sequence
  • Genome, Human
  • Sulfites
  • Messenger RNA
  • Up-Regulation
  • Cancer Gene Expression Regulation
  • Wilms Tumour
  • Promoter Regions
  • Tamoxifen
  • Breast Cancer
  • Transcriptional Activation
  • DNA-Binding Proteins
  • Genomic Imprinting
  • YY1 Transcription Factor
  • Zinc Fingers
  • DNA Methylation
  • Sweden
  • Mutation
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CTCF (cancer-related)

Isoda T, Morio T, Takagi M
Noncoding RNA transcription at enhancers and genome folding in cancer.
Cancer Sci. 2019; 110(8):2328-2336 [PubMed] Free Access to Full Article Related Publications
Changes of nuclear localization of lineage-specific genes from a transcriptionally inert to permissive environment are a crucial step in establishing the identity of a cell. Noncoding RNA transcription-mediated genome folding and activation of target gene expression have been found in a variety of cell types. Noncoding RNA ThymoD (thymocyte differentiation factor) transcription at superenhancers is essential for mouse T-cell lineage commitment. The cessation of ThymoD transcription abolishes transcription-mediated demethylation, recruiting looping factors such as the cohesin complex, CCCTC-binding factor (CTCF), ultimately leading to the phenotype of severe combined immunodeficiency and T-cell leukemia/lymphoma. In this review, we describe the functional role of RNA polymerase II-mediated transcription at enhancers and in genome folding. We also highlight the involvement of faulty activation or suppression of enhancer transcription and enhancer-promoter interaction in cancer development.

Yang M, Vesterlund M, Siavelis I, et al.
Proteogenomics and Hi-C reveal transcriptional dysregulation in high hyperdiploid childhood acute lymphoblastic leukemia.
Nat Commun. 2019; 10(1):1519 [PubMed] Free Access to Full Article Related Publications
Hyperdiploidy, i.e. gain of whole chromosomes, is one of the most common genetic features of childhood acute lymphoblastic leukemia (ALL), but its pathogenetic impact is poorly understood. Here, we report a proteogenomic analysis on matched datasets from genomic profiling, RNA-sequencing, and mass spectrometry-based analysis of >8,000 genes and proteins as well as Hi-C of primary patient samples from hyperdiploid and ETV6/RUNX1-positive pediatric ALL. We show that CTCF and cohesin, which are master regulators of chromatin architecture, display low expression in hyperdiploid ALL. In line with this, a general genome-wide dysregulation of gene expression in relation to topologically associating domain (TAD) borders were seen in the hyperdiploid group. Furthermore, Hi-C of a limited number of hyperdiploid childhood ALL cases revealed that 2/4 cases displayed a clear loss of TAD boundary strength and 3/4 showed reduced insulation at TAD borders, with putative leukemogenic effects.

Zhou Y, Gerrard DL, Wang J, et al.
Temporal dynamic reorganization of 3D chromatin architecture in hormone-induced breast cancer and endocrine resistance.
Nat Commun. 2019; 10(1):1522 [PubMed] Free Access to Full Article Related Publications
Recent studies have demonstrated that chromatin architecture is linked to the progression of cancers. However, the roles of 3D structure and its dynamics in hormone-dependent breast cancer and endocrine resistance are largely unknown. Here we report the dynamics of 3D chromatin structure across a time course of estradiol (E2) stimulation in human estrogen receptor α (ERα)-positive breast cancer cells. We identified subsets of temporally highly dynamic compartments predominantly associated with active open chromatin and found that these highly dynamic compartments showed higher alteration in tamoxifen-resistant breast cancer cells. Remarkably, these compartments are characterized by active chromatin states, and enhanced ERα binding but decreased transcription factor CCCTC-binding factor (CTCF) binding. We finally identified a set of ERα-bound promoter-enhancer looping genes enclosed within altered domains that are enriched with cancer invasion, aggressiveness or metabolism signaling pathways. This large-scale analysis expands our understanding of high-order temporal chromatin reorganization underlying hormone-dependent breast cancer.

Nagai LAE, Park SJ, Nakai K
Analyzing the 3D chromatin organization coordinating with gene expression regulation in B-cell lymphoma.
BMC Med Genomics. 2019; 11(Suppl 7):127 [PubMed] Related Publications
BACKGROUND: Eukaryotes compact chromosomes densely and non-randomly, forming three-dimensional structures. Alterations of the chromatin structures are often associated with diseases. In particular, aggressive cancer development from the disruption of the humoral immune system presents abnormal gene regulation which is accompanied by chromatin reorganizations. How the chromatin structures orchestrate the gene expression regulation is still poorly understood. Herein, we focus on chromatin dynamics in normal and abnormal B cell lymphocytes, and investigate its functional impact on the regulation of gene expression.
METHODS: We conducted an integrative analysis using publicly available multi-omics data that include Hi-C, RNA-seq and ChIP-seq experiments with normal B cells, lymphoma and ES cells. We processed and re-analyzed the data exhaustively and combined different scales of genome structures with transcriptomic and epigenetic features.
RESULTS: We found that the chromatin organizations are highly preserved among the cells. 5.2% of genes at the specific repressive compartment in normal pro-B cells were switched to the permissive compartment in lymphoma along with increased gene expression. The genes are involved in B-cell related biological processes. Remarkably, the boundaries of topologically associating domains were not enriched by CTCF motif, but significantly enriched with Prdm1 motif that is known to be the key factor of B-cell dysfunction in aggressive lymphoma.
CONCLUSIONS: This study shows evidence of a complex relationship between chromatin reorganization and gene regulation. However, an unknown mechanism may exist to restrict the structural and functional changes of genomic regions and cognate genes in a specific manner. Our findings suggest the presence of an intricate crosstalk between the higher-order chromatin structure and cancer development.

Perreault AA, Sprunger DM, Venters BJ
Epigenetic and transcriptional profiling of triple negative breast cancer.
Sci Data. 2019; 6:190033 [PubMed] Free Access to Full Article Related Publications
The human HCC1806 cell line is frequently used as a preclinical model for triple negative breast cancer (TNBC). Given that dysregulated epigenetic mechanisms are involved in cancer pathogenesis, emerging therapeutic strategies target chromatin regulators, such as histone deacetylases. A comprehensive understanding of the epigenome and transcription profiling in HCC1806 provides the framework for evaluating efficacy and molecular mechanisms of epigenetic therapies. Thus, to study the interplay of transcription and chromatin in the HCC1806 preclinical model, we performed nascent transcription profiling using Precision Run-On coupled to sequencing (PRO-seq). Additionally, we mapped the genome-wide locations for RNA polymerase II (Pol II), the histone variant H2A.Z, seven histone modifications, and CTCF using ChIP-exo. ChIP-exonuclease (ChIP-exo) is a refined version of ChIP-seq with near base pair precision mapping of protein-DNA interactions. In this Data Descriptor, we present detailed information on experimental design, data generation, quality control analysis, and data validation. We discuss how these data lay the foundation for future analysis to understand the relationship between the nascent transcription and chromatin.

Cuevas D, Valls J, Gatius S, et al.
Targeted sequencing with a customized panel to assess histological typing in endometrial carcinoma.
Virchows Arch. 2019; 474(5):585-598 [PubMed] Related Publications
The two most frequent types of endometrial cancer (EC) are endometrioid (EEC) and serous carcinomas (SC). Differential diagnosis between them is not always easy. A subset of endometrial cancers shows misleading microscopical features, which cause problems in differential diagnosis, and may be a good scenario for next-generation sequencing. Previous studies have assessed the usefulness of targeted sequencing with panels of generic cancer-associated genes in EC histological typing. Based on the analysis of TCGA (The Cancer Genome Atlas), EEC and SC have different mutational profiles. In this proof of principle study, we have performed targeted sequencing analysis with a customized panel, based on the TCGA mutational profile of EEC and SC, in a series of 24 tumors (16 EEC and 8 SC). Our panel comprised coding and non-coding sequences of the following genes: ABCC9, ARID1A, ARID5B, ATR, BCOR, CCND1, CDH19, CHD4, COL11A1, CSDE1, CSMD3, CTCF, CTNNB1, EP300, ERBB2, FBXW7, FGFR2, FOXA2, KLLN, KMT2B, KRAS, MAP3K4, MKI67, NRAS, PGAP3, PIK3CA, PIK3R1, PPP2R1A, PRPF18, PTEN, RPL22, SCARNA11, SIN3A, SMARCA4, SPOP, TAF1, TP53, TSPYL2, USP36, and WRAP53. Targeted sequencing validation by Sanger sequencing and immunohistochemistry was performed in a group of genes. POLE mutation status was assessed by Sanger sequencing. The most mutated genes were PTEN (93.7%), ARID1A (68.7%), PIK3CA (50%), and KMT2B (43.7%) for EEC, and TP53 (87.5%), PIK3CA (50%), and PPP2R1A (25%) for SC. Our panel allowed correct classification of all tumors in the two categories (EEC, SC). Coexistence of mutations in PTEN, ARID1A, and KMT2B was diagnostic of EEC. On the other hand, absence of PTEN, ARID1A, and KMT2B mutations in the presence of TP53 mutation was diagnostic of SC. This proof of concept study demonstrates the suitability of targeted sequencing with a customized endometrial cancer gene panel as an additional tool for confirming histological typing.

Brix DM, Tvingsholm SA, Hansen MB, et al.
Release of transcriptional repression via ErbB2-induced, SUMO-directed phosphorylation of myeloid zinc finger-1 serine 27 activates lysosome redistribution and invasion.
Oncogene. 2019; 38(17):3170-3184 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
HER2/ErbB2 activation turns on transcriptional processes that induce local invasion and lead to systemic metastasis. The early transcriptional changes needed for ErbB2-induced invasion are poorly understood. Here, we link ErbB2 activation to invasion via ErbB2-induced, SUMO-directed phosphorylation of a single serine residue, S27, of the transcription factor myeloid zinc finger-1 (MZF1). Utilizing an antibody against MZF1-pS27, we show that the phosphorylation of S27 correlates significantly (p < 0.0001) with high-level expression of ErbB2 in primary invasive breast tumors. Phosphorylation of MZF1-S27 is an early response to ErbB2 activation and results in increased transcriptional activity of MZF1. It is needed for the ErbB2-induced expression of MZF1 target genes CTSB and PRKCA, and invasion of single-cells from ErbB2-expressing breast cancer spheroids. The phosphorylation of MZF1-S27 is preceded by poly-SUMOylation of K23, which can make S27 accessible to efficient phosphorylation by PAK4. Based on our results, we suggest for an activation mechanism where phosphorylation of MZF1-S27 triggers MZF1 dissociation from its transcriptional repressors such as the CCCTC-binding factor (CTCF). Our findings increase understanding of the regulation of invasive signaling in breast cancer by uncovering a detailed biological mechanism of how ErbB2 activation can rapidly lead to its invasion-promoting target gene expression and invasion.

Bailey CG, Metierre C, Feng Y, et al.
CTCF Expression is Essential for Somatic Cell Viability and Protection Against Cancer.
Int J Mol Sci. 2018; 19(12) [PubMed] Article available free on PMC after 01/10/2019 Related Publications
CCCTC-binding factor (CTCF) is a conserved transcription factor that performs diverse roles in transcriptional regulation and chromatin architecture. Cancer genome sequencing reveals diverse acquired mutations in

Kim TN, Kim WT, Jeong MS, et al.
Short rare minisatellite variant of BORIS-MS2 is related to bladder cancer susceptibility.
Genes Genomics. 2019; 41(2):249-256 [PubMed] Related Publications
BACKGROUND: BORIS/CTCFL, a paralog of CTCF and member of the cancer-testicular antigen family, is abnormally activated in multiple cancers.
OBJECTIVE: We investigated the relationship between polymorphic variants of the BORIS minisatellite 2 (BORIS-MS2), located within the 5' upstream promoter region of BORIS, and bladder cancer.
METHODS: We used case-control study with 516 controls and 113 bladder cancer patients. To evaluate whether minisatellite variants play a role in BORIS expression, we examined the transcript levels of a reporter gene linked to these minisatellites in cell lines. We also examined BORIS expression in cancerous and non-cancerous bladder tissue.
RESULTS: A statistically significant association was identified between the short rare allele (13-repeat) and bladder cancer incidence (odds ratio (OR) 2.97, 95% confidence interval (CI) [1.14, 7.74]; P = 0.020). In particular, short rare alleles in the younger group (aged < 65) were associated with statistically significant increase in bladder cancer risk (OR 5.38, CI [1.32, 21.87]; P = 0.01). The BORIS-MS2 region acted as a negative regulator, and the expression level of the luciferase reporter in bladder cancer cells was less effectively inhibited than in normal cells. Furthermore, the expression of BORIS mRNA significantly differed (P < 0.05) between normal and cancerous muscle-invasive bladder cancer tissues, and relationship to clinical parameters was observed.
CONCLUSIONS: The short rare allele of BORIS-MS2 could be used to identify bladder cancer risk. BORIS expression levels have been shown to increase with the progression of bladder cancer, could be used as a biomarker for its progression.

Guo X, Dean A
CRISPR/Cas9 offers a new tool for studying the role of chromatin architecture in disease pathogenesis.
Genome Biol. 2018; 19(1):185 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
A recent study used CRISPR/Cas9 to reveal long-range looping between disease-related genes and their regulatory elements that is mediated by the CCCTC-binding factor (CTCF) in prostate cancer.

Michel BC, D'Avino AR, Cassel SH, et al.
A non-canonical SWI/SNF complex is a synthetic lethal target in cancers driven by BAF complex perturbation.
Nat Cell Biol. 2018; 20(12):1410-1420 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Mammalian SWI/SNF chromatin remodelling complexes exist in three distinct, final-form assemblies: canonical BAF (cBAF), PBAF and a newly characterized non-canonical complex (ncBAF). However, their complex-specific targeting on chromatin, functions and roles in disease remain largely undefined. Here, we comprehensively mapped complex assemblies on chromatin and found that ncBAF complexes uniquely localize to CTCF sites and promoters. We identified ncBAF subunits as synthetic lethal targets specific to synovial sarcoma and malignant rhabdoid tumours, which both exhibit cBAF complex (SMARCB1 subunit) perturbation. Chemical and biological depletion of the ncBAF subunit, BRD9, rapidly attenuates synovial sarcoma and malignant rhabdoid tumour cell proliferation. Importantly, in cBAF-perturbed cancers, ncBAF complexes maintain gene expression at retained CTCF-promoter sites and function in a manner distinct from fusion oncoprotein-bound complexes. Together, these findings unmask the unique targeting and functional roles of ncBAF complexes and present new cancer-specific therapeutic targets.

Loukinov D
Targeting CTCFL/BORIS for the immunotherapy of cancer.
Cancer Immunol Immunother. 2018; 67(12):1955-1965 [PubMed] Related Publications
Cancer vaccines have great potential in the fight against metastatic malignancies. Current anti-tumor immunotherapy is hindered by existing tolerance to tumor-associated antigens (TAA) and tumor escape using various mechanisms, highlighting the need for improved targets for immunotherapy. The cancer-testis antigen CTCFL/BORIS was discovered 16 years ago and possesses all features necessary for an ideal TAA. Recently CTCFL/BORIS has received additional attention as a target expressed in cancer stem cells (CSC). These cells drive tumor growth recurrence, metastasis, and treatment resistance. CTCFL/BORIS silencing leads to senescence and death of CSC. Therefore, an immunotherapeutic strategy that targets CTCFL/BORIS may lead to the selective destruction of CSC and potential eradication of metastatic disease. The high immunotherapeutic potential of CTCFL/BORIS antigen was shown in a stringent 4T1 mouse model of breast cancer. Using these highly metastatic, poorly immunogenic carcinoma cells inoculated into T-helper2 prone mice, we showed that DC fed with recombinant CTCFL/BORIS as an immunogen inhibited tumor growth and reduced the number of metastases in distant organs. About 20% of CTCFL/BORIS immunized animals were tumor free. 50% of animals remained metastasis free. Those having metastasis showed at least tenfold fewer metastases compared to controls. In a rat model of breast cancer, we showed that alphavirus-based CTCFL/BORIS immunotherapy was capable of cancer elimination as we were able to cure 50% of animals. Based on the above data, we believe that translation of CTCFL/BORIS-targeting immunotherapeutic strategies to the clinic will provide new avenues for improving survival of breast cancer patients with advanced metastatic disease.

Guo Y, Perez AA, Hazelett DJ, et al.
CRISPR-mediated deletion of prostate cancer risk-associated CTCF loop anchors identifies repressive chromatin loops.
Genome Biol. 2018; 19(1):160 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: Recent genome-wide association studies (GWAS) have identified more than 100 loci associated with increased risk of prostate cancer, most of which are in non-coding regions of the genome. Understanding the function of these non-coding risk loci is critical to elucidate the genetic susceptibility to prostate cancer.
RESULTS: We generate genome-wide regulatory element maps and performed genome-wide chromosome confirmation capture assays (in situ Hi-C) in normal and tumorigenic prostate cells. Using this information, we annotate the regulatory potential of 2,181 fine-mapped prostate cancer risk-associated SNPs and predict a set of target genes that are regulated by prostate cancer risk-related H3K27Ac-mediated loops. We next identify prostate cancer risk-associated CTCF sites involved in long-range chromatin loops. We use CRISPR-mediated deletion to remove prostate cancer risk-associated CTCF anchor regions and the CTCF anchor regions looped to the prostate cancer risk-associated CTCF sites, and we observe up to 100-fold increases in expression of genes within the loops when the prostate cancer risk-associated CTCF anchor regions are deleted.
CONCLUSIONS: We identify GWAS risk loci involved in long-range loops that function to repress gene expression within chromatin loops. Our studies provide new insights into the genetic susceptibility to prostate cancer.

Razavi P, Chang MT, Xu G, et al.
The Genomic Landscape of Endocrine-Resistant Advanced Breast Cancers.
Cancer Cell. 2018; 34(3):427-438.e6 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
We integrated the genomic sequencing of 1,918 breast cancers, including 1,501 hormone receptor-positive tumors, with detailed clinical information and treatment outcomes. In 692 tumors previously exposed to hormonal therapy, we identified an increased number of alterations in genes involved in the mitogen-activated protein kinase (MAPK) pathway and in the estrogen receptor transcriptional machinery. Activating ERBB2 mutations and NF1 loss-of-function mutations were more than twice as common in endocrine resistant tumors. Alterations in other MAPK pathway genes (EGFR, KRAS, among others) and estrogen receptor transcriptional regulators (MYC, CTCF, FOXA1, and TBX3) were also enriched. Altogether, these alterations were present in 22% of tumors, mutually exclusive with ESR1 mutations, and associated with a shorter duration of response to subsequent hormonal therapies.

Aitken SJ, Ibarra-Soria X, Kentepozidou E, et al.
CTCF maintains regulatory homeostasis of cancer pathways.
Genome Biol. 2018; 19(1):106 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
BACKGROUND: CTCF binding to DNA helps partition the mammalian genome into discrete structural and regulatory domains. Complete removal of CTCF from mammalian cells causes catastrophic genome dysregulation, likely due to widespread collapse of 3D chromatin looping and alterations to inter- and intra-TAD interactions within the nucleus. In contrast, Ctcf hemizygous mice with lifelong reduction of CTCF expression are viable, albeit with increased cancer incidence. Here, we exploit chronic Ctcf hemizygosity to reveal its homeostatic roles in maintaining genome function and integrity.
RESULTS: We find that Ctcf hemizygous cells show modest but robust changes in almost a thousand sites of genomic CTCF occupancy; these are enriched for lower affinity binding events with weaker evolutionary conservation across the mouse lineage. Furthermore, we observe dysregulation of the expression of several hundred genes, which are concentrated in cancer-related pathways, and are caused by changes in transcriptional regulation. Chromatin structure is preserved but some loop interactions are destabilized; these are often found around differentially expressed genes and their enhancers. Importantly, the transcriptional alterations identified in vitro are recapitulated in mouse tumors and also in human cancers.
CONCLUSIONS: This multi-dimensional genomic and epigenomic profiling of a Ctcf hemizygous mouse model system shows that chronic depletion of CTCF dysregulates steady-state gene expression by subtly altering transcriptional regulation, changes which can also be observed in primary tumors.

Kaiser VB, Semple CA
Chromatin loop anchors are associated with genome instability in cancer and recombination hotspots in the germline.
Genome Biol. 2018; 19(1):101 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
BACKGROUND: Chromatin loops form a basic unit of interphase nuclear organization, with chromatin loop anchor points providing contacts between regulatory regions and promoters. However, the mutational landscape at these anchor points remains under-studied. Here, we describe the unusual patterns of somatic mutations and germline variation associated with loop anchor points and explore the underlying features influencing these patterns.
RESULTS: Analyses of whole genome sequencing datasets reveal that anchor points are strongly depleted for single nucleotide variants (SNVs) in tumours. Despite low SNV rates in their genomic neighbourhood, anchor points emerge as sites of evolutionary innovation, showing enrichment for structural variant (SV) breakpoints and a peak of SNVs at focal CTCF sites within the anchor points. Both CTCF-bound and non-CTCF anchor points harbour an excess of SV breakpoints in multiple tumour types and are prone to double-strand breaks in cell lines. Common fragile sites, which are hotspots for genome instability, also show elevated numbers of intersecting loop anchor points. Recurrently disrupted anchor points are enriched for genes with functions in cell cycle transitions and regions associated with predisposition to cancer. We also discover a novel class of CTCF-bound anchor points which overlap meiotic recombination hotspots and are enriched for the core PRDM9 binding motif, suggesting that the anchor points have been foci for diversity generated during recent human evolution.
CONCLUSIONS: We suggest that the unusual chromatin environment at loop anchor points underlies the elevated rates of variation observed, marking them as sites of regulatory importance but also genomic fragility.

Lupey-Green LN, Caruso LB, Madzo J, et al.
PARP1 Stabilizes CTCF Binding and Chromatin Structure To Maintain Epstein-Barr Virus Latency Type.
J Virol. 2018; 92(18) [PubMed] Article available free on PMC after 10/09/2019 Related Publications
Epstein Barr virus (EBV) is a potentially oncogenic gammaherpesvirus that establishes a chronic, latent infection in memory B cells. The EBV genome persists in infected host cells as a chromatinized episome and is subject to chromatin-mediated regulation. Binding of the host insulator protein CTCF to the EBV genome has an established role in maintaining viral latency type. CTCF is posttranslationally modified by the host enzyme PARP1. PARP1, or poly(ADP-ribose) polymerase 1, catalyzes the transfer of a poly(ADP-ribose) (PAR) moiety from NAD

Wei X, Yu L, Jin X, et al.
Identification of open chromosomal regions and key genes in prostate cancer via integrated analysis of DNase‑seq and RNA‑seq data.
Mol Med Rep. 2018; 18(2):2245-2252 [PubMed] Related Publications
Prostate cancer is a type of adenocarcinoma arising from the peripheral zone of the prostate gland, and metastasized prostate cancer is incurable with the current available therapies. The present study aimed to identify open chromosomal regions and differentially expressed genes (DEGs) associated with prostate cancer development. The DNase sequencing data (GSE33216) and RNA sequencing data (GSE22260) were downloaded from the Gene Expression Omnibus database. DNase I hypersensitive sites were detected and analyzed. Subsequently, DEGs were identified and their potential functions were enriched. Finally, upstream regulatory elements of DEGs were predicted. In LNCaP cells, following androgen receptor activation, 244 upregulated and 486 downregulated open chromosomal regions were identified. However, only 1% of the open chromosomal regions were dynamically altered. The 41 genes with upregulated open chromosomal signals within their promoter regions were primarily enriched in biological processes. Additionally, 211 upregulated and 150 downregulated DEGs were identified in prostate cancer, including eight transcription factors (TFs). Finally, nine regulatory elements associated with prostate cancer were predicted. In particular, inhibitor of DNA binding 1 HLH protein (ID1) was the only significantly upregulated TF which exhibited motif enrichment in the promoter regions of upregulated genes. CCCTC‑binding factor (CTCF) and ELK1 ETS transcription factor (ELK1), enriched in the open promoter regions of downregulated genes, were potential upstream regulatory elements. Furthermore, reverse transcription‑quantitative polymerase chain reaction analysis confirmed that ID1 expression was significantly upregulated in LNCaP cells and 5α‑dihydrotestosterone (DHT)‑treated LNCaP cells compared with that in BPH1 cells, while CTCF and ELK1 expression was significantly downregulated in LNCaP cells and DHT‑treated LNCaP cells. In conclusion, ID1, CTCF and ELK1 may be associated with prostate cancer, and may be potential therapeutic targets for the treatment of this disease.

Aljarbou F, Almousa N, Bazzi M, et al.
The expression of telomere-related proteins and DNA damage response and their association with telomere length in colorectal cancer in Saudi patients.
PLoS One. 2018; 13(6):e0197154 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
BACKGROUND: Colorectal cancer is the leading cause of cancer-related deaths in Saudi Arabia. Cancer has a multifactorial nature and can be described as a disease of altered gene expression. The profiling of gene expression has been used to identify cancer subtypes and to predict patients' responsiveness. Telomere-associated proteins that regulate telomere biology are essential molecules in cancer development. Thus, the present study examined their contributions to colorectal cancer progression in Saudi patients.
METHODS: The expression of hTERT, TRF1, TRF2, POT1, ATR, ATM, Chk1 and Chk2 were measured via real-time PCR in matched cancerous and adjacent tissues of CRC patients. The protein level of hTERT, TRF1, TRF2, ATR, ATM, Chk1 and Chk2 were measured using immunohistochemistry. A region of hTERT core promoter was sequenced via Sanger sequencing. Methylation of CTCF binding site was examined via methylation-specific PCR. Finally, the length of telomere was estimated using q-PCR.
RESULTS: Our results showed that POT1, ATR, Chk1 and Chk2 show increased expression in CRC relative to the adjacent mucosa. The expression levels of each gene were associated with clinicopathological characteristics of patients with CRC. There was a positive correlation between the age of the patients and hTERT expression. Regarding tumor site, telomere length, ATR, ATM and Chk1 were shown to be altered. No somatic mutation was detected in hTERT core promoter, and no differences in methylation patterns at CTCF binding site in the promoter between normal and cancer tissues.
CONCLUSION: Analysis of targeted genes expression in colorectal cancer based on the clinical variables revealed that tumor location and age could have a role in gene expression and telomere length variations and this could be taken under consideration during CRC diagnosis and therapy. Other epigenetic mechanisms could influence hTERT expression in cancers. Our findings warrant further validation through experiments involving a larger number of patients.

Sun X, Wang X, Tang Z, et al.
Transcription factor profiling reveals molecular choreography and key regulators of human retrotransposon expression.
Proc Natl Acad Sci U S A. 2018; 115(24):E5526-E5535 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
Transposable elements (TEs) represent a substantial fraction of many eukaryotic genomes, and transcriptional regulation of these factors is important to determine TE activities in human cells. However, due to the repetitive nature of TEs, identifying transcription factor (TF)-binding sites from ChIP-sequencing (ChIP-seq) datasets is challenging. Current algorithms are focused on subtle differences between TE copies and thus bias the analysis to relatively old and inactive TEs. Here we describe an approach termed "MapRRCon" (mapping repeat reads to a consensus) which allows us to identify proteins binding to TE DNA sequences by mapping ChIP-seq reads to the TE consensus sequence after whole-genome alignment. Although this method does not assign binding sites to individual insertions in the genome, it provides a landscape of interacting TFs by capturing factors that bind to TEs under various conditions. We applied this method to screen TFs' interaction with L1 in human cells/tissues using ENCODE ChIP-seq datasets and identified 178 of the 512 TFs tested as bound to L1 in at least one biological condition with most of them (138) localized to the promoter. Among these L1-binding factors, we focused on Myc and CTCF, as they play important roles in cancer progression and 3D chromatin structure formation. Furthermore, we explored the transcriptomes of The Cancer Genome Atlas breast and ovarian tumor samples in which a consistent anti-/correlation between L1 and Myc/CTCF expression was observed, suggesting that these two factors may play roles in regulating L1 transcription during the development of such tumors.

Luo H, Wang F, Zha J, et al.
CTCF boundary remodels chromatin domain and drives aberrant
Blood. 2018; 132(8):837-848 [PubMed] Article available free on PMC after 10/09/2019 Related Publications

Guo YA, Chang MM, Huang W, et al.
Mutation hotspots at CTCF binding sites coupled to chromosomal instability in gastrointestinal cancers.
Nat Commun. 2018; 9(1):1520 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
Tissue-specific driver mutations in non-coding genomic regions remain undefined for most cancer types. Here, we unbiasedly analyze 212 gastric cancer (GC) whole genomes to identify recurrently mutated non-coding regions in GC. Applying comprehensive statistical approaches to accurately model background mutational processes, we observe significant enrichment of non-coding indels (insertions/deletions) in three gastric lineage-specific genes. We further identify 34 mutation hotspots, of which 11 overlap CTCF binding sites (CBSs). These CBS hotspots remain significant even after controlling for a genome-wide elevated mutation rate at CBSs. In 3 out of 4 tested CBS hotspots, mutations are nominally associated with expression change of neighboring genes. CBS hotspot mutations are enriched in tumors showing chromosomal instability, co-occur with neighboring chromosomal aberrations, and are common in gastric (25%) and colorectal (19%) tumors but rare in other cancer types. Mutational disruption of specific CBSs may thus represent a tissue-specific mechanism of tumorigenesis conserved across gastrointestinal cancers.

Hall AW, Battenhouse AM, Shivram H, et al.
Bivalent Chromatin Domains in Glioblastoma Reveal a Subtype-Specific Signature of Glioma Stem Cells.
Cancer Res. 2018; 78(10):2463-2474 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
Glioblastoma multiforme (GBM) can be clustered by gene expression into four main subtypes associated with prognosis and survival, but enhancers and other gene-regulatory elements have not yet been identified in primary tumors. Here, we profiled six histone modifications and

Amaral PP, Leonardi T, Han N, et al.
Genomic positional conservation identifies topological anchor point RNAs linked to developmental loci.
Genome Biol. 2018; 19(1):32 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
BACKGROUND: The mammalian genome is transcribed into large numbers of long noncoding RNAs (lncRNAs), but the definition of functional lncRNA groups has proven difficult, partly due to their low sequence conservation and lack of identified shared properties. Here we consider promoter conservation and positional conservation as indicators of functional commonality.
RESULTS: We identify 665 conserved lncRNA promoters in mouse and human that are preserved in genomic position relative to orthologous coding genes. These positionally conserved lncRNA genes are primarily associated with developmental transcription factor loci with which they are coexpressed in a tissue-specific manner. Over half of positionally conserved RNAs in this set are linked to chromatin organization structures, overlapping binding sites for the CTCF chromatin organiser and located at chromatin loop anchor points and borders of topologically associating domains (TADs). We define these RNAs as topological anchor point RNAs (tapRNAs). Characterization of these noncoding RNAs and their associated coding genes shows that they are functionally connected: they regulate each other's expression and influence the metastatic phenotype of cancer cells in vitro in a similar fashion. Furthermore, we find that tapRNAs contain conserved sequence domains that are enriched in motifs for zinc finger domain-containing RNA-binding proteins and transcription factors, whose binding sites are found mutated in cancers.
CONCLUSIONS: This work leverages positional conservation to identify lncRNAs with potential importance in genome organization, development and disease. The evidence that many developmental transcription factors are physically and functionally connected to lncRNAs represents an exciting stepping-stone to further our understanding of genome regulation.

Baribault C, Ehrlich KC, Ponnaluri VKC, et al.
Developmentally linked human DNA hypermethylation is associated with down-modulation, repression, and upregulation of transcription.
Epigenetics. 2018; 13(3):275-289 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
DNA methylation can affect tissue-specific gene transcription in ways that are difficult to discern from studies focused on genome-wide analyses of differentially methylated regions (DMRs). To elucidate the variety of associations between differentiation-related DNA hypermethylation and transcription, we used available epigenomic and transcriptomic profiles from 38 human cell/tissue types to focus on such relationships in 94 genes linked to hypermethylated DMRs in myoblasts (Mb). For 19 of the genes, promoter-region hypermethylation in Mb (and often a few heterologous cell types) was associated with gene repression but, importantly, DNA hypermethylation was absent in many other repressed samples. In another 24 genes, DNA hypermethylation overlapped cryptic enhancers or super-enhancers and correlated with down-modulated, but not silenced, gene expression. However, such methylation was absent, surprisingly, in both non-expressing samples and highly expressing samples. This suggests that some genes need DMR hypermethylation to help repress cryptic enhancer chromatin only when they are actively transcribed. For another 11 genes, we found an association between intergenic hypermethylated DMRs and positive expression of the gene in Mb. DNA hypermethylation/transcription correlations similar to those of Mb were evident sometimes in diverse tissues, such as aorta and brain. Our findings have implications for the possible involvement of methylated DNA in Duchenne's muscular dystrophy, congenital heart malformations, and cancer. This epigenomic analysis suggests that DNA methylation is not simply the inevitable consequence of changes in gene expression but, instead, is often an active agent for fine-tuning transcription in association with development.

Miano V, Ferrero G, Rosti V, et al.
Luminal lncRNAs Regulation by ERα-Controlled Enhancers in a Ligand-Independent Manner in Breast Cancer Cells.
Int J Mol Sci. 2018; 19(2) [PubMed] Article available free on PMC after 10/09/2019 Related Publications
Estrogen receptor-α (ERα) is a ligand-inducible protein which mediates estrogenic hormones signaling and defines the luminal BC phenotype. Recently, we demonstrated that even in absence of ligands ERα (apoERα) binds chromatin sites where it regulates transcription of several protein-coding and lncRNA genes. Noteworthy, apoERα-regulated lncRNAs marginally overlap estrogen-induced transcripts, thus representing a new signature of luminal BC genes. By the analysis of H3K27ac enrichment in hormone-deprived MCF-7 cells, we defined a set of Super Enhancers (SEs) occupied by apoERα, including one mapped in proximity of the DSCAM-AS1 lncRNA gene. This represents a paradigm of apoERα activity since its expression is largely unaffected by estrogenic treatment, despite the fact that E2 increases ERα binding on DSCAM-AS1 promoter. We validated the enrichment of apoERα, p300, GATA3, FoxM1 and CTCF at both DSCAM-AS1 TSS and at its associated SE by ChIP-qPCR. Furthermore, by analyzing MCF-7 ChIA-PET data and by 3C assays, we confirmed long range chromatin interaction between the SE and the DSCAM-AS1 TSS. Interestingly, CTCF and p300 binding showed an enrichment in hormone-depleted medium and in the presence of ERα, elucidating the dynamics of the estrogen-independent regulation of DSCAM-AS1 expression. The analysis of this lncRNA provides a paradigm of transcriptional regulation of a luminal specific apoERα regulated lncRNA.

Gong Y, Lazaris C, Sakellaropoulos T, et al.
Stratification of TAD boundaries reveals preferential insulation of super-enhancers by strong boundaries.
Nat Commun. 2018; 9(1):542 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
The metazoan genome is compartmentalized in areas of highly interacting chromatin known as topologically associating domains (TADs). TADs are demarcated by boundaries mostly conserved across cell types and even across species. However, a genome-wide characterization of TAD boundary strength in mammals is still lacking. In this study, we first use fused two-dimensional lasso as a machine learning method to improve Hi-C contact matrix reproducibility, and, subsequently, we categorize TAD boundaries based on their insulation score. We demonstrate that higher TAD boundary insulation scores are associated with elevated CTCF levels and that they may differ across cell types. Intriguingly, we observe that super-enhancers are preferentially insulated by strong boundaries. Furthermore, we demonstrate that strong TAD boundaries and super-enhancer elements are frequently co-duplicated in cancer patients. Taken together, our findings suggest that super-enhancers insulated by strong TAD boundaries may be exploited, as a functional unit, by cancer cells to promote oncogenesis.

Zhao X, Li D, Huang D, et al.
Risk-Associated Long Noncoding RNA FOXD3-AS1 Inhibits Neuroblastoma Progression by Repressing PARP1-Mediated Activation of CTCF.
Mol Ther. 2018; 26(3):755-773 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
Neuroblastoma (NB) is the most common extracranial tumor in childhood. Recent studies have implicated the emerging roles of long noncoding RNAs (lncRNAs) in tumorigenesis and aggressiveness. However, the functions and targets of risk-associated lncRNAs in NB progression still remain to be determined. Herein, through mining of public microarray datasets, we identify lncRNA forkhead box D3 antisense RNA 1 (FOXD3-AS1) as an independent prognostic marker for favorable outcome of NB patients. FOXD3-AS1 is downregulated in NB tissues and cell lines, and ectopic expression of FOXD3-AS1 induces neuronal differentiation and decreases the aggressiveness of NB cells in vitro and in vivo. Mechanistically, as a nuclear lncRNA, FOXD3-AS1 interacts with poly(ADP-ribose) polymerase 1 (PARP1) to inhibit the poly(ADP-ribosyl)ation and activation of CCCTC-binding factor (CTCF), resulting in derepressed expression of downstream tumor-suppressive genes. Rescue experiments indicate that FOXD3-AS1 harbors tumor-suppressive properties by inhibiting the oncogenic roles of PARP1 or CTCF and plays crucial roles in all-trans-retinoic-acid-mediated therapeutic effects on NB. Administration of FOXD3-AS1 construct or siRNAs against PARP1 or CTCF reduces the tumor growth and prolongs the survival of nude mice. These findings suggest that as a risk-associated lncRNA, FOXD3-AS1 inhibits the progression of NB through repressing PARP1-mediated CTCF activation.

Pang Y, Zhao J, Fowdur M, et al.
To Explore the Mechanism of the GRM4 Gene in Osteosarcoma by RNA Sequencing and Bioinformatics Approach.
Med Sci Monit Basic Res. 2018; 24:16-25 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
BACKGROUND Glutamate metabotropic receptor 4 (GRM4) has been correlated with the pathogenesis of osteosarcoma. The objective of this study was to explore the underlying molecular mechanism of GRM4 in osteosarcoma. MATERIAL AND METHODS The expression levels of GRM4 in four human osteosarcoma cell lines and hFOB1.19 cells were examined by real-time quantitative PCR (RT-qPCR). The U2OS cells of the highest GRM4 expression were transfected with lentivirus-mediated small interfering RNA (siRNA). The differentially expressed genes (DEGs) after GRM4 gene silencing were screened through RNA sequencing, and analyzed by bioinformatics. Additionally, the transcription factors (TFs) targeting GRM4 were predicted and the downstream protein-protein interaction (PPI) network was constructed using the bioinformatics approach. RESULTS A total of 51 significant DEGs were obtained, including 14 upregulated and 37 downregulated DEGs. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the DEGs indicated that four significant enrichment pathways were obtained. A total of six TFs that could be involved in the transcriptional regulation of GRM4 were detected. The results showed that 182 genes in the PPI network were significantly enriched in 14 pathways. The chemokines and chemokine receptors were found to be significantly enriched in three pathways. CONCLUSIONS The DEGs in the four significant enrichment pathways might participate in the development and progression of osteosarcoma through GRM4. The results revealed that EGR1 and CTCF are probably involved in the transcriptional regulation of GRM4, which participates in the progress of osteosarcoma by interacting with chemokines and their receptors.

Tian Y, Wang G, Hu Q, et al.
AML1/ETO trans-activates c-KIT expression through the long range interaction between promoter and intronic enhancer.
J Cell Biochem. 2018; 119(4):3706-3715 [PubMed] Related Publications
The AML1/ETO onco-fusion protein is crucial for the genesis of t(8;21) acute myeloid leukemia (AML) and is well documented as a transcriptional repressor through dominant-negative effect. However, little is known about the transactivation mechanism of AML1/ETO. Through large cohort of patient's expression level data analysis and a series of experimental validation, we report here that AML1/ETO transactivates c-KIT expression through directly binding to and mediating the long-range interaction between the promoter and intronic enhancer regions of c-KIT. Gene expression analyses verify that c-KIT expression is significantly high in t(8;21) AML. Further ChIP-seq analysis and motif scanning identify two regulatory regions located in the promoter and intronic enhancer region of c-KIT, respectively. Both regions are enriched by co-factors of AML1/ETO, such as AML1, CEBPe, c-Jun, and c-Fos. Further luciferase reporter assays show that AML1/ETO trans-activates c-KIT promoter activity through directly recognizing the AML1 motif and the co-existence of co-factors. The induction of c-KIT promoter activity is reinforced with the existence of intronic enhancer region. Furthermore, ChIP-3C-qPCR assays verify that AML1/ETO mediates the formation of DNA-looping between the c-KIT promoter and intronic enhancer region through the long-range interaction. Collectively, our data uncover a novel transcriptional activity mechanism of AML1/ETO and enrich our knowledge of the onco-fusion protein mediated transcription regulation.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. CTCF, Cancer Genetics Web: http://www.cancer-genetics.org/CTCF.htm Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 31 August, 2019     Cancer Genetics Web, Established 1999