scholarly journals Cancer-specific CTCF binding facilitates oncogenic transcriptional dysregulation

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Celestia Fang ◽  
Zhenjia Wang ◽  
Cuijuan Han ◽  
Stephanie L. Safgren ◽  
Kathryn A. Helmin ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Genome Organization ◽  
Target Genes ◽  
Lymphoblastic Leukemia ◽  
Three Dimensional ◽  
Leukemia Cell ◽  
Dna Looping ◽  
Ctcf Binding ◽  
Gene Promoters ◽  
Human Cancers

Abstract Background The three-dimensional genome organization is critical for gene regulation and can malfunction in diseases like cancer. As a key regulator of genome organization, CCCTC-binding factor (CTCF) has been characterized as a DNA-binding protein with important functions in maintaining the topological structure of chromatin and inducing DNA looping. Among the prolific binding sites in the genome, several events with altered CTCF occupancy have been reported as associated with effects in physiology or disease. However, hitherto there is no comprehensive survey of genome-wide CTCF binding patterns across different human cancers. Results To dissect functions of CTCF binding, we systematically analyze over 700 CTCF ChIP-seq profiles across human tissues and cancers and identify cancer-specific CTCF binding patterns in six cancer types. We show that cancer-specific lost and gained CTCF binding events are associated with altered chromatin interactions, partially with DNA methylation changes, and rarely with sequence mutations. While lost bindings primarily occur near gene promoters, most gained CTCF binding events exhibit enhancer activities and are induced by oncogenic transcription factors. We validate these findings in T cell acute lymphoblastic leukemia cell lines and patient samples and show that oncogenic NOTCH1 induces specific CTCF binding and they cooperatively activate expression of target genes, indicating transcriptional condensation phenomena. Conclusions Specific CTCF binding events occur in human cancers. Cancer-specific CTCF binding can be induced by other transcription factors to regulate oncogenic gene expression. Our results substantiate CTCF binding alteration as a functional epigenomic signature of cancer.

scholarly journals Cancer-specific CTCF binding facilitates oncogenic transcriptional dysregulation

2020 ◽  
Author(s):  
Celestia Fang ◽  
Zhenjia Wang ◽  
Cuijuan Han ◽  
Stephanie L. Safgren ◽  
Kathryn A. Helmin ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Transcription Factors ◽  
Genome Organization ◽  
Target Genes ◽  
Lymphoblastic Leukemia ◽  
Three Dimensional ◽  
Dna Looping ◽  
Ctcf Binding ◽  
Gene Promoters ◽  
Comprehensive Survey

AbstractBackgroundThe three-dimensional genome organization is critical for gene regulation and can malfunction in diseases like cancer. As a key regulator of genome organization, CCCTC-binding factor (CTCF) has been characterized as a DNA-binding protein with important functions in maintaining the topological structure of chromatin and inducing DNA looping. Among the prolific binding sites in the genome, several events with altered CTCF occupancy have been reported as associated with effects in physiology or disease. However, there is no hitherto a comprehensive survey of genome-wide CTCF binding patterns across different human cancers.ResultsTo dissect functions of CTCF binding, we systematically analyze over 700 CTCF ChIP-seq profiles across human tissues and cancers and identify cancer-specific CTCF binding patterns in six cancer types. We show that cancer-specific lost and gained CTCF binding events are associated with altered chromatin interactions in patient samples, but not always with DNA methylation changes or sequence mutations. While lost bindings primarily occur near gene promoters, most gained CTCF binding events are induced by oncogenic transcription factors and exhibit enhancer activities. We validate these findings in T-cell acute lymphoblastic leukemia and show that oncogenic NOTCH1 induces specific CTCF binding and they cooperatively activate expression of target genes, indicating transcriptional condensation phenomena.ConclusionsCancer-specific CTCF binding events are not always associated with DNA methylation changes or mutations, but can be induced by other transcription factors to regulate oncogenic gene expression. Our results substantiate CTCF binding alteration as a functional epigenomic signature of cancer.

Androgen receptor: acting in the three-dimensional chromatin landscape of prostate cancer cells

2011 ◽  
Vol 5 (1) ◽  
Author(s):  
Harri Makkonen ◽  
Jorma J. Palvimo
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Binding Sites ◽  
Target Genes ◽  
Three Dimensional ◽  
Regulatory Elements ◽  
Gene Promoters ◽  
Loop Formation ◽  
Prostate Cancer Cells

AbstractAndrogen receptor (AR) acts as a hormone-controlled transcription factor that conveys the messages of both natural and synthetic androgens to the level of genes and gene programs. Defective AR signaling leads to a wide array of androgen insensitivity disorders, and deregulated AR function, in particular overexpression of AR, is involved in the growth and progression of prostate cancer. Classic models of AR action view AR-binding sites as upstream regulatory elements in gene promoters or their proximity. However, recent wider genomic screens indicate that AR target genes are commonly activated through very distal chromatin-binding sites. This highlights the importance of long-range chromatin regulation of transcription by the AR, shifting the focus from the linear gene models to three-dimensional models of AR target genes and gene programs. The capability of AR to regulate promoters from long distances in the chromatin is particularly important when evaluating the role of AR in the regulation of genes in malignant prostate cells that frequently show striking genomic aberrations, especially gene fusions. Therefore, in addition to the mechanisms of DNA loop formation between the enhancer bound ARs and the transcription apparatus at the target core promoter, the mechanisms insulating distally bound ARs from promiscuously making contacts and activating other than their normal target gene promoters are critical for proper physiological regulation and thus currently under intense investigation. This review discusses the current knowledge about the AR action in the context of gene aberrations and the three-dimensional chromatin landscape of prostate cancer cells.

scholarly journals PICOT binding to chromatin-associated EED negatively regulates cyclin D2 expression by increasing H3K27me3 at the CCND2 gene promoter

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Pinakin Pandya ◽  
Minesh Jethva ◽  
Eitan Rubin ◽  
Ramon Y. Birnbaum ◽  
Alex Braiman ◽  
...  
Keyword(s):  
Target Genes ◽  
Patient Survival ◽  
Leukemia Cell ◽  
Gene Promoter ◽  
Human Tumors ◽  
Polycomb Group ◽  
The Cancer Genome Atlas ◽  
Polycomb Group Protein ◽  
Cyclin D2 ◽  
Human Cancers

Abstract Protein kinase C (PKC)-interacting cousin of thioredoxin (PICOT; also termed glutaredoxin 3 (Grx3; Glrx3)) is a ubiquitous protein that can interact with the embryonic ectoderm development (EED) protein via each of its two C-terminal PICOT/Grx homology domains. Since EED is a Polycomb-Group protein and a core component of the polycomb repressive complex 2 (PRC2), we tested the involvement of PICOT in the regulation of PRC2-mediated H3 lysine 27 trimethylation (H3K27me3), transcription and translation of selected PRC2 target genes. A fraction of the cellular PICOT protein was found in the nuclei of leukemia cell lines, where it was associated with the chromatin. In addition, PICOT coimmunoprecipitated with chromatin-residing EED derived from Jurkat and COS-7 cell nuclei. PICOT knockdown led to a reduced H3K27me3 mark and a decrease in EED and EZH2 at the CCND2 gene promoter. In agreement, PICOT-deficient T cells exhibited a significant increase in CCND2 mRNA and protein expression. Since elevated expression levels of PICOT were reported in several different tumors and correlated in the current studies with decreased transcription and translation of the CCND2 gene, we tested whether this opposite correlation exists in human cancers. Data from the Cancer Genome Atlas (TCGA) database indicated statistically significant negative correlation between PICOT and CCND2 in eight different human tumors where the highest correlation was in lung (p = 8.67E−10) and pancreatic (p = 1.06E−5) adenocarcinoma. Furthermore, high expression of PICOT and low expression of CCND2 correlated with poor patient survival in five different types of human tumors. The results suggest that PICOT binding to chromatin-associated EED modulates the H3K27me3 level at the CCND2 gene promoter which may be one of the potential mechanisms for regulation of cyclin D2 expression in tumors. These findings also indicate that a low PICOT/CCND2 expression ratio might serve as a good predictor of patient survival in selected human cancers.

scholarly journals EZH2 knockdown upregulates expression of the genes involved in T-ALL cell differentiation

2021 ◽  
Author(s):  
Sahar Safaei ◽  
Behzad Baradaran ◽  
Behzad Mansoori ◽  
Masoumeh Fardi ◽  
Elham Baghbani ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factors ◽  
Cell Differentiation ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Leukemia Cell Line ◽  
Aberrant Expression ◽  
Expression Levels ◽  
Ezh2 Expression

Background: EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit), as one of the polycyclic group proteins (PcGs), is an epigenetic regulator that plays a crucial role in the pathophysiology of hematologic malignancies through regulating cell differentiation. Also, it is well known that aberrant expression of specific transcription factors can be involved in the pathogenesis of various cancers. Objective: Herein, we aimed to suppress EZH2 expression in MOLT-4 cells, T-ALL (T cell acute lymphoblastic leukemia) cell line, and evaluate the role of EZH2 on the expression of transcription factors that regulate T cell maturation, differentiation, and apoptosis. Methods: EZH2-siRNA was transfected into MOLT-4 cells, and the expression levels of EZH2, NOTCH1, TCF1, IKZF1, and NFATC1 were measured using real-time PCR. The MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay was performed to study the effect of EZH2 knockdown on MOLT-4 cell viability. The apoptosis rate of EZH2-siRNA transfected cells was assessed by flow cytometry. The interaction of mentioned genes was investigated using STRING and GO (gene ontology). Results: Our results have shown that EZH2-siRNA transfection can substantially decrease EZH2 expression in MOLT-4 cells. Besides, EZH2 suppression can upregulate NOTCH1, TCF1, IKZF1, and NFATC1 expression levels. EZH2 knockdown does not affect the viability and apoptosis of MOLT-4 cells. The most remarkable protein-protein interaction of EZH2 has been with NOTCH1. Besides, GO analysis has demonstrated that EZH2, NOTCH1, TCF1, IKZF1, and NFATC1 were located within nucleoplasm and can regulate RNA polymerase II-mediated transcription. Conclusion: Our results have shown that MOLT-4 cells harbor increased expression of EZH2 in comparison with normal human T cells. EZH2 knockdown can upregulate the expression of the transcription factors involved in T cell differentiation. Thus, EZH2 can halt the differentiation of immature lymphoblastic T cells.

Genome-Wide Mapping of Binding Sites and Networks of Potential Target Genes of the Fusion Oncogene ETV6/RUNX1 in Acute Lymphoblastic Leukemia in Childhood

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3776-3776
Author(s):  
Katja Kaulfuss ◽  
Thomas Heiden ◽  
Jochen Hecht ◽  
Karl Seeger
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Target Genes ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Chromatin Condensation ◽  
Chromosomal Translocation ◽  
Cellular Transformation ◽  
Gene Promoters ◽  
Childhood All

Abstract Acute lymphoblastic leukemia (ALL) in childhood, a clinically and biologically heterogeneous disease, represents the most common malignant disease in childhood. Approximately 20-25% of B-cell precursor ALL (BCP-ALL) carry the cryptic chromosomal translocation t(12;21)(p13;q22), the most common reciprocal chromosomal translocation in childhood ALL. This translocation combines two transcription factors and essential regulators of normal hematopoiesis, ETV6 and RUNX1, into the fusion oncogene ETV6/RUNX1 (E/R; synonym TEL/AML1). Recent studies in various animal models have strengthened the view that E/R positive cells give rise to preleukemic clones with a differentiation block in the pro/pre-B stage of B cell development that, after acquisition of additional mutations, may transform into full malignancy. Regarding the molecular mechanism by which the chimeric fusion protein E/R causes gene expression changes, it is assumed that E/R binds with the runt homology domain of RUNX1 (RHD, DNA-binding domain) to RUNX1 target sequences of gene promoters and recruits corepressors and histone deacetylases through its ETV6 portion, leading to chromatin condensation and transcriptional repression. Thus, E/R appears to act mainly as an epigenetic repressor of genes that are normally activated by RUNX1. However, the precise mechanism of cellular transformation and the identity of E/R target genes are largely unknown. Therefore, we used chromatin immunoprecipitation (ChIP), followed by next generation sequencing (ChIP-Seq) to identify E/R target genes in the E/R positive BCP-ALL cell lines REH and UoC-B6 as well as in primary patient material from children with relapsed E/R positive ALL. We were able to detect a core gene set of 335 candidate target genes common to all samples analyzed. Those genes could be assigned to 15 significantly overrepresented KEGG pathways (e.g. cell cycle, pathways in cancer, hematopoietic cell lineage and B cell receptor signaling pathway). The results show, besides target genes already reported in the literature such as EPOR, MPO and IGLL1, numerous not previously described candidate E/R target genes, such as LEF1, E2F2, FLT3, FGFR1 and RUNX1 that are potentially important in the pathogenesis of E/R positive ALL and may lead to new treatment options. Disclosures No relevant conflicts of interest to declare.

scholarly journals CTCF: the protein, the binding partners, the binding sites and their chromatin loops

2013 ◽  
Vol 368 (1620) ◽  
pp. 20120369 ◽  
Author(s):  
Sjoerd Johannes Bastiaan Holwerda ◽  
Wouter de Laat
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Rna Polymerase Ii ◽  
Binding Sites ◽  
Ctcf Binding ◽  
Chromatin Domain ◽  
Gene Promoters ◽  
Tissue Specific ◽  
Chromatin Loops ◽  
Exact Function

CTCF has it all. The transcription factor binds to tens of thousands of genomic sites, some tissue-specific, others ultra-conserved. It can act as a transcriptional activator, repressor and insulator, and it can pause transcription. CTCF binds at chromatin domain boundaries, at enhancers and gene promoters, and inside gene bodies. It can attract many other transcription factors to chromatin, including tissue-specific transcriptional activators, repressors, cohesin and RNA polymerase II, and it forms chromatin loops. Yet, or perhaps therefore, CTCF's exact function at a given genomic site is unpredictable. It appears to be determined by the associated transcription factors, by the location of the binding site relative to the transcriptional start site of a gene, and by the site's engagement in chromatin loops with other CTCF-binding sites, enhancers or gene promoters. Here, we will discuss genome-wide features of CTCF binding events, as well as locus-specific functions of this remarkable transcription factor.

scholarly journals Spatial genome re-organization between fetal and adult hematopoietic stem cells

2019 ◽  
Author(s):  
C Chen ◽  
W Yu ◽  
J Tober ◽  
P Gao ◽  
B He ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Target Genes ◽  
Three Dimensional ◽  
Gene Promoters ◽  
Loss Of Function ◽  
Dynamic Interactions ◽  
Hematopoietic Stem ◽  
3D Genome ◽  
Chromatin Interactions

AbstractFetal hematopoietic stem cells (HSCs) undergo a developmental switch to become adult HSCs. The functional properties of the HSCs change dramatically during this switch, including their cycling behavior, hematopoietic lineage outputs and proliferation rate. The relationship between three-dimensional (3D) genome organization, epigenomic state, and transcriptome is poorly understood during this critical developmental transition. Here we conducted a comprehensive survey of the 3D genome, epigenome and transcriptome of fetal and adult HSCs in mouse. We found that chromosomal compartments and topologically associating domains (TAD) are largely conserved between fetal and adult HSCs. However, there is a global trend of increased compartmentalization and TAD boundary strength in adult HSCs. In contrast, dynamics of intra-TAD chromatin interactions is much higher and more widespread, involving over a thousand gene promoters and distal enhancers. Such dynamic interactions target genes involved in cell cycle, metabolism, and hematopoiesis. These developmental-stage-specific enhancer-promoter interactions appear to be mediated by different sets of transcription factors in fetal and adult HSCs, such as TCF3 and MAFB in fetal HSCs, versus NR4A1 and GATA3 in adult HSCs. Loss-of-function studies of TCF3 confirms the role of TCF3 in mediating condition-specific enhancer-promoter interactions and gene regulation in fetal HSCs. In summary, our data suggest that the fetal-to-adult transition is accompanied by extensive changes in intra-TAD chromatin interactions that target genes underlying the phenotypic differences between fetal and adult HSCs.

scholarly journals Taiji: System-level identification of key transcription factors reveals transcriptional waves in mouse embryonic development

2019 ◽  
Vol 5 (3) ◽  
pp. eaav3262 ◽  
Author(s):  
Kai Zhang ◽  
Mengchi Wang ◽  
Ying Zhao ◽  
Wei Wang
Keyword(s):  
Transcription Factors ◽  
Embryonic Development ◽  
Regulatory Networks ◽  
Target Genes ◽  
Developmental Stages ◽  
Three Dimensional ◽  
Cell Types ◽  
System Level ◽  
Transcriptional Regulatory Networks ◽  
Developmental Progress

Transcriptional regulation is pivotal to the specification of distinct cell types during embryonic development. However, it still lacks a systematic way to identify key transcription factors (TFs) orchestrating the temporal and tissue specificity of gene expression. Here, we integrated epigenomic and transcriptomic data to reveal key regulators from two cells to postnatal day 0 in mouse embryogenesis. We predicted three-dimensional chromatin interactions in 12 tissues across eight developmental stages, which facilitates linking TFs to their target genes for constructing transcriptional regulatory networks. To identify driver TFs, we developed a new algorithm, dubbed Taiji, to assess the global influence of each TF and systematically uncovered TFs critical for lineage-specific and stage-dependent tissue specification. We have also identified TF combinations that function in spatiotemporal order to form transcriptional waves regulating developmental progress. Furthermore, lacking stage-specific TF combinations suggests a distributed timing strategy to orchestrate the coordination between tissues during embryonic development.

scholarly journals Genome-wide targeting of the epigenetic regulatory protein CTCF to gene promoters by the transcription factor TFII-I

2015 ◽  
Vol 112 (7) ◽  
pp. E677-E686 ◽  
Author(s):  
Rodrigo Peña-Hernández ◽  
Maud Marques ◽  
Khalid Hilmi ◽  
Teijun Zhao ◽  
Amine Saad ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Rna Polymerase Ii ◽  
Transcription Initiation ◽  
Cellular Response ◽  
Target Genes ◽  
Regulatory Protein ◽  
Metabolic Stress ◽  
Ctcf Binding ◽  
Gene Promoters ◽  
The Impact

CCCTC-binding factor (CTCF) is a key regulator of nuclear chromatin structure and gene regulation. The impact of CTCF on transcriptional output is highly varied, ranging from repression to transcriptional pausing and transactivation. The multifunctional nature of CTCF may be directed solely through remodeling chromatin architecture. However, another hypothesis is that the multifunctional nature of CTCF is mediated, in part, through differential association with protein partners having unique functions. Consistent with this hypothesis, our mass spectrometry analyses of CTCF interacting partners reveal a previously undefined association with the transcription factor general transcription factor II-I (TFII-I). Biochemical fractionation of CTCF indicates that a distinct CTCF complex incorporating TFII-I is assembled on DNA. Unexpectedly, we found that the interaction between CTCF and TFII-I is essential for directing CTCF to the promoter proximal regulatory regions of target genes across the genome, particularly at genes involved in metabolism. At genes coregulated by CTCF and TFII-I, we find knockdown of TFII-I results in diminished CTCF binding, lack of cyclin-dependent kinase 8 (CDK8) recruitment, and an attenuation of RNA polymerase II phosphorylation at serine 5. Phenotypically, knockdown of TFII-I alters the cellular response to metabolic stress. Our data indicate that TFII-I directs CTCF binding to target genes, and in turn the two proteins cooperate to recruit CDK8 and enhance transcription initiation.

scholarly journals Impact of 3D genome organization, guided by cohesin and CTCF looping, on sex-biased chromatin interactions and gene expression in mouse liver

2020 ◽  
Author(s):  
Bryan J Matthews ◽  
David J Waxman
Keyword(s):  
Gene Expression ◽  
Sex Differences ◽  
Binding Sites ◽  
Genome Organization ◽  
Mouse Liver ◽  
Ctcf Binding ◽  
Gene Promoters ◽  
3D Genome ◽  
Chromatin Interactions ◽  
The Impact

Abstract Several thousand sex-differential distal enhancers have been identified in mouse liver; however, their links to sex-biased genes and the impact of any sex-differences in nuclear organization and chromatin interactions are unknown. To address these issues, we first characterized 1,847 mouse liver genomic regions showing significant sex differential occupancy by cohesin and CTCF, two key 3D nuclear organizing factors. These sex-differential binding sites were primarily distal to sex-biased genes but rarely generated sex-differential TAD (topologically associating domain) or intra-TAD loop anchors, and were sometimes found in TADs without sex-biased genes. A substantial subset of sex-biased cohesin-non-CTCF binding sites, but not sex-biased cohesin-and-CTCF binding sites, overlapped sex-biased enhancers. Cohesin depletion reduced the expression of male-biased genes with distal, but not proximal, sex-biased enhancers by >10-fold, implicating cohesin in long-range enhancer interactions regulating sex-biased genes. Using circularized chromosome conformation capture-based sequencing (4C-seq), we showed that sex differences in distal sex-biased enhancer - promoter interactions are common. Intra-TAD loops with sex-independent cohesin-and-CTCF anchors conferred sex specificity to chromatin interactions indirectly, by insulating sex-biased enhancer - promoter contacts and by bringing sex-biased genes into closer proximity to sex-biased enhancers. Furthermore, sex-differential chromatin interactions involving sex-biased gene promoters, enhancers, and lncRNAs were associated with sex-biased binding of cohesin and/or CTCF. These studies elucidate how 3D genome organization impacts sex-biased gene expression in a non-reproductive tissue through both direct and indirect effects of cohesin and CTCF looping on distal enhancer interactions with sex-differentially expressed genes.

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