- Open Access
The DEK oncoprotein binds to highly and ubiquitously expressed genes with a dual role in their transcriptional regulation
© Sandén et al.; licensee BioMed Central Ltd. 2014
Received: 11 March 2014
Accepted: 9 September 2014
Published: 12 September 2014
The DEK gene is highly expressed in a wide range of cancer cells, and a recurrent translocation partner in acute myeloid leukemia. While DEK has been identified as one of the most abundant proteins in human chromatin, its function and binding properties are not fully understood.
We performed ChIP-seq analysis in the myeloid cell line U937 and coupled it with epigenetic and gene expression analysis to explore the genome-wide binding pattern of DEK and its role in gene regulation.
We show that DEK preferentially binds to open chromatin, with a low degree of DNA methylation and scarce in the heterochromatin marker H3K9me3 but rich in the euchromatin marks H3K4me2/3, H3K27ac and H3K9ac. More specifically, DEK binding is predominantly located at the transcription start sites of highly transcribed genes and a comparative analysis with previously established transcription factor binding patterns shows a similarity with that of RNA polymerase II. Further bioinformatic analysis demonstrates that DEK mainly binds to genes that are ubiquitously expressed across tissues. The functional significance of DEK binding was demonstrated by knockdown of DEK by shRNA, resulting in both significant upregulation and downregulation of DEK-bound genes.
We find that DEK binds to transcription start sites with a dual role in activation and repression of highly and ubiquitously expressed genes.
The DEK oncogene is highly expressed in many types of cancers, including breast, ovarian, bladder, colon, and skin cancer as well as acute myeloid leukemia [1–3]. High DEK expression is also associated with advanced disease and poor prognosis [4–6]. No mutations have been reported and upregulation may occur through copy gains  or transcriptional activation by upstream regulators such as E2F-1 , NF-Y , YY-1  and ERα . The DEK gene is also part of the t(6;9) chromosomal translocation resulting in the DEK-NUP214 fusion gene, which is found in 1% of acute myeloid leukemias and promotes cellular proliferation and transformation [10, 11].
What is known of the role of DEK in cancer biology is multifaceted. The expression is generally high in rapidly proliferating cells and knockdown of DEK by shRNA reduces the proliferation of cell lines from several tissues [1, 12]. Inhibition of DEK is sufficient to drive melanoma cells into senescence whereas overexpression prolongs cellular lifespan [13, 14]. In several cell types, DEK expression is reduced during cellular differentiation and depletion of DEK promotes the differentiation of both cell lines and primary cells [15, 16]. Conversely, overexpression of DEK causes a shift in keratinocytes from a differentiated to a proliferative state . Many studies have also implicated DEK in apoptosis, although with differing roles depending on the cellular context. In HeLa cells, DEK depletion leads to apoptosis through p53 stabilization, whereas knockdown of DEK in melanoma cells causes downregulation of the anti-apoptotic protein MCL-1 [2, 17]. Reduced expression of DEK has also been shown to increase the sensitivity to apoptotic agents . DEK is thus implicated in several essential oncogenic mechanisms, including both proliferation, differentiation and apoptosis.
Consistent with a role in these processes, DEK contributes to cellular transformation. This has been most strikingly demonstrated in keratinocytes, where cells overexpressing DEK in addition to the HRAS, HPV E6 and E7 oncogenes display increased potential to form colonies in soft agar and tumors when transplanted into mice. The transformed cells are more sensitive to depletion of DEK than the surrounding normal tissue, raising the possibility of oncogene addiction and DEK as a drug target. This notion is further supported by the finding that DEK knockout mice are less prone to develop tumors when challenged with carcinogens .
DEK is a structurally unique and highly conserved protein with emerging roles in epigenetic and transcriptional regulation. The DEK protein changes chromatin topology by introducing positive supercoils and assembles DNA and histones into chromatin [20, 21]. It has also been shown to sustain the levels of the repressive histone mark H3K9me3 and inhibit several activating histone acetyl transferases [22, 23]. Concordantly, DEK has been deemed essential for the preservation of transcriptionally inactive heterochromatin . However, immunofluorescent imaging as well as immunoprecipitation shows accumulation of DEK in regions of transcriptionally active euchromatin [20, 24]. The reported roles of DEK in transcriptional regulation are similarly paradoxical. DEK counteracts transcriptional activation by SET, NFκB, P/CAF and p300 and is found in a repression complex with Daxx [23, 25–27]. But it is also a coactivator of U2AF and the Drosophila ecdysone receptor, enhances the transcriptional activity of AP-2α and C/EBPα, and accumulates during transcriptional activation of the CR2 gene [20, 28–31]. To investigate the seemingly conflicting reports on the geography of DEK binding and its role in gene regulation, we performed a genome-wide analysis of global DEK binding by ChIP-seq and knocked down DEK with shRNA to analyze changes in gene expression. We find that DEK binds to transcription start sites of highly and ubiquitously transcribed genes and that DEK binding can serve to either promote or repress transcription.
DEK binds close to the transcription start site
DEK binds to highly and commonly expressed genes
DEK binds to open chromatin
DEK binding is enriched among certain sets of genes
DEK binds to genes involved in multiple cellular functions
Gene ontology term
2.7 × 10−6
mRNA metabolic process
1.8 × 10−8
5.3 × 10−3
Ubiquitin-dependent protein catabolic process
4.9 × 10−3
Cellular macromolecular complex assembly
5.0 × 10−5
7.2 × 10−4
Interspecies interaction between organisms
2.8 × 10−3
Protein complex biogenesis
7.9 × 10−5
4.7 × 10−4
Cellular catabolic process
2.5 × 10−3
5.0 × 10−4
DEK binds to DNA with motifs for major transcriptional regulators
Motif e value
Match P value
1.5 × 10−41
5.6 × 10−22
9.3 × 10−20
1.3 × 10−18
1.5 × 10−13
6.7 × 10−12
3.0 × 10−9
1.0 × 10−8
3.4 × 10−8
6.9 × 10−6
4.5 × 10−5
3.5 × 10−3
7.6 × 10−3
DEK binding correlates with gene expression
DEK expression correlates with the expression of other genes
Correlations in the AML dataset
Correlations in the MILE dataset
This study provides a genome-wide map of DEK binding in myeloid cells. We show that DEK does not bind uniformly to long stretches of the genome, as previously suggested by the high amounts of DEK bound to chromatin . Instead, we demonstrate that DEK binding is highly distinct and centered around transcription start sites. We continue to show that DEK mainly binds to highly expressed genes and that the accumulation of binding around the transcription start site positively correlates with the transcription of the gene. These findings are in concert with a previous study of a single gene locus, which found that DEK binding to the promoter of the complement receptor 2 gene is 2–3 fold higher in a cell line expressing the gene than in a cell line without expression and in which DEK was shown to be recruited to the promoter upon induction of gene expression . Furthermore, our findings are consistent with previous reports that DEK contributes to positive supercoiling of the DNA structure, which opens up the chromatin to allow access to the transcriptional machinery and is a characteristic of highly transcribed genes [21, 40]. The correlation between DEK binding and gene expression is further underlined by our finding that out of the 2642 binding patterns in the Encode database, the DEK binding pattern is most similar to that of RNA polymerase II.
Interestingly, we found that the DEK binding pattern not only resembles that of RNA polymerase II in hematopoietic cells but also in highly different cell types. In a comparison with the complete collection of POL2 bindings patterns in Encode, DEK was one of the factors with the highest degree of similarity. The DEK binding pattern actually scored higher than most POL2 binding patterns in terms of similarity with overall POL2 binding. This shows that DEK binds to genes that are commonly expressed across cell types, which could explain the ubiquitous expression of DEK in human tissues. Genes that are expressed in very different cell types generally contribute to common functions such as cellular organization and metabolism. Gene ontology analysis confirmed that genes bound by DEK are involved in basic cellular functions such as catabolism, biogenesis and chromatin organization. Many of these processes are not only fundamental to normal cells but must also be deregulated in order for cancer cells to produce the macromolecules and the energy needed for their high proliferation. Accelerating basic cellular functions could thus be a way by which DEK contributes to carcinogenesis. This notion would be compatible with the previous observation that DEK is essential for tumor cells but dispensable for their normal counterparts . We also show that DEK binds to genes involved in cell cycle regulation and gene expression, processes with obvious implications for cancer biology. Since the binding patterns collected in the Encode database are mainly derived from transformed cell lines, some of the commonly expressed genes encode the proteins conferring the cancer phenotype. We show that the genes bound by DEK are also enriched for genes involved in cell cycle regulation and gene expression, which could mediate the oncogenic function of DEK.
Previous studies have provided contradictory indications regarding the association of DEK with euchromatin and heterochromatin. Based on immunofluorescence imaging, DEK co-localizes with regions of open chromatin containing acetylated histone H4 . It also co-precipitates with the activating histone marks H3K4me2 and H3K4me3. Contrarily, other reports have indicated DEK as essential for the maintenance of heterochromatin by strengthening the binding between heterochromatin protein 1α and the heterochromatin marker H3K9me3. Here, we show that DEK binding overlaps with histone marks found in euchromatin and with genes carrying a low degree of DNA methylation. We thus conclude that DEK preferentially binds to euchromatin and more specifically to transcription start sites of euchromatic genes.
DEK has been shown to bind to chromatin in a manner dependent on the structure rather than the sequence of the DNA, based on the finding that DEK accumulates at sites of supercoiled and four-way junction DNA . However, sequence-specific binding to the peri-ets site of the HIV-2 enhancer has been demonstrated . To determine the sequence-specificity of the genome-wide DEK binding, we performed motif analysis of the bound sequences. The analysis identified the most significantly enriched motif as that of the hematopoietic transcription factor PU.1. However, given that PU.1 is a major transcription factor in these cells, many of its target genes coincide with the highly expressed genes bound by RNA polymerase II. Since the comparison with the Encode experiments shows that the binding pattern of DEK is more similar to the binding pattern of RNA polymerase II than to that of PU.1, it is more likely that the binding to genes with PU.1 motifs is a consequence of their high expression than that PU.1 would be the major determinant of DEK binding. We also identified several previously uncharacterized motifs. However, it is unlikely that any of these is a common DEK motif as none of them were nearly as significantly enriched as the PU.1 motif. Thus, we find that DNA sequence does not predict DEK binding as well as gene expression.
The role of DEK binding in gene expression is still ambiguous, with reports of contributions to either activation or repression of single genes under different conditions. Our finding that knockdown of DEK leads to both upregulation and downregulation of DEK-bound genes suggests that DEK has a dual role in gene regulation in that it can either promote or repress transcription of different genes in the same cellular context. The determinants of the effect of DEK on transcription are still unknown but could potentially include phosphorylation by casein kinase 2, which has been shown to alter but not abolish the association between DEK and chromatin . Another possible model is one where DEK contributes to either activation or repression depending on the cofactors that bind at the gene regulatory site.
To further examine the importance of DEK in gene regulation in primary leukemic cells, we constructed a network model of gene expression and found that out of the 1246 analyzed factors, DEK was the factor with the third highest number of correlated genes. This suggests that DEK may have a broad set of targets, consistent with our findings that DEK binds to many highly and commonly expressed genes. Furthermore, it strongly suggests that DEK is important for gene regulation and may play a major role in the gene regulatory pathways that govern cancer cells. Characterizing the precise mechanistics of DEK-mediated gene regulation will be an important challenge for future research and a key to understanding the role of DEK in cancer biology and its potential as a therapeutic target.
Materials and methods
The U937 cell line (ATCC, Manassas, VA, USA) was cultured in RPMI 1640 medium (Life Technologies, Carlsbad, CA, USA) supplemented with 10% fetal bovine serum (Life Technologies). Primary CD34+ cells were obtained from human umbilical cord blood collected at Skåne University Hospital. The mononuclear cell population was isolated by separation on Lymphoprep (Axis-Shield PoC AS, Oslo, Norway) and CD34+ cells were subsequently selected using the Indirect CD34 MicroBead Kit (Miltenyi Biotec, Bergisch Gladbach, Germany). The cells were grown in StemSpan SFEM medium (Stemcell Technologies, Vancouver, Canada) supplemented by 20% fetal bovine serum and the CC100 cytokine cocktail (Stemcell Technologies).
Chromatin immunoprecipitation was performed on U937 cells using the Magna-ChIP A/G Chromatin Immunoprecipitation Kit (Merck Millipore, Billerica, MA, USA) after crosslinking with 1% formaldehyde for 15 min. Chromatin shearing was achieved by sonication in a Bioruptor UCD-200 (Diagenode, Liège, Belgium). Immunoprecipitation was performed with 10 μg of DEK antibody (Abcam, Cambridge, UK; product code ab74975) per million cells. Immunoprecipitated DNA was sequenced by the Science for Life Laboratory in Stockholm, Sweden with an Illumina HiSeq 2000 as paired-end reads to 100 bp with a minimum of 18 million reads per sample. The Illumina OLB v1.9 was used for base conversion, the Bowtie 2 software  was used for the alignment of reads to the hg19 reference genome and peak calling was performed with the MACS software v1.4.1 . Default parameters were used throughout the process. Two independent ChIP-seq experiments were performed under identical conditions and the peaks found in both experiments were used for all subsequent analyses. Non-precipitated chromatin was used as negative control. Validation was performed by real-time PCR analysis of DNA immunoprecipitated with the DEK antibody, showing enrichment of DNA corresponding to the predicted binding sites in the S100A9 (fold enrichment 2.4) and VIM (fold enrichment 1.8) genes and a lack of enrichment of DNA corresponding to the IRF8 gene (fold enrichment -3.1), which was determined by the ChIP-seq analysis to not be bound by DEK. The raw data from the ChIP-seq analysis is available through the Gene Expression Omnibus data repository, with the accession number “GSE60692”.
Binding to genomic elements
The “Genomic annotation of ChIP-seq peaks” tool in the Nebula software package  was used with default parameters to find the closest gene to each DEK peak and calculate the distance from the transcription start site to the middle of the peak. The same tool was used to determine the genomic elements to which DEK binds, using default settings where promoters are designated as the 2.000 bp upstream of the transcription start site and enhancers are designated as the 30.000 bp upstream of the TSS. As control, random genomic sequences were generated by a random draw with replacement from a square-distribution across all genomic positions.
Cap analysis of gene expression
Absolute gene expression levels for all genes in the U937 cell line were determined by Cap Analysis of Gene Expression (CAGE) in a study by the FANTOM5 consortium . All genes were ordered by absolute expression and divided into bins of one thousand, for which we calculated the number of genes where DEK binds within 1000 bp from the transcription start site. For further analysis, all DEK-bound genes were divided into four categories according to their expression; no (0), low (0–10), intermediate (10–100) or high (>100) expression. For each category, the distances to the nearest transcription start sites were calculated as described above.
Correlation with existing ChIP-seq binding patterns
where weight1i and weight2i are the score assigned basepair i in the two tracks compared, respectively, and nbasepairs is the total number of basepairs in the hg19 assembly of the human genome. DEK binding was correlated with open chromatin status by comparison of the DEK binding pattern with the Encode tracks designated OpenChromSynth, each containing a synthesis of results from ChIP-seq, FAIRE-seq and DNAse hypersensitivity analysis in the examined cell type. The binding patterns of different histone marks in the K562 cell line were obtained from the Broad Histone dataset in Encode. Statistical testing of the enrichment of tracks representing either RNA polymerase II or OpenChromSynth among the most similar binding patterns to that of DEK was performed using the RenderCat software, as previously described .
DNA methylation array
Microarray-based DNA methylation analysis was performed with the Infinium HumanMethylation27 BeadChip (Illumina) by the BEA core facility at Karolinska Institute. Genomic DNA from U937 cells was extracted using the QIAamp DNA mini kit (Qiagen) and bisulfite converted using the Zymo EZ DNA methylation Kit (Zymo Research, Irvine, CA). Subsequently, the DNA was subjected to the Illumina Infinium HD Methylation assay including whole genome amplification and enzymatic fragmentation before hybridization to the BeadChip. Arrays were scanned and the signals processed in Genome Studio module 1.8. The methylation grade for each gene was calculated as the average of the corresponding probes. The methylation of the genes to which DEK binds within 1000 bp of the transcription start site was then compared to the methylation of the entire genome. The raw data from the DNA methylation analysis is available through the Gene Expression Omnibus data repository, with the accession number “GSE60734”.
Knockdown of DEK by shRNA
Two shRNAs in H1 lentiviral vectors targeting the DEK transcript were a kind gift from Dr David Markovitz . Lentiviral particles were harvested after calcium phosphate transfection of 293 T cells (ATCC) with the respective shRNA constructs, gag-pol and the RD114 envelope gene. For lentiviral transduction, non-tissue culture coated plates were coated with retronectin (Takara, Otsu, Japan) and blocked with 2% bovine serum albumin (Sigma-Aldrich, St. Louis, MO, USA) for 30 min at room temperature. Subsequently, virus-containing medium was added and the plates were centrifuged at 1000 × g for 60 min at 4°C before the cells were added and incubated at 37°C for 48 h, after which they were sorted by FACS based on the expression of the GFP marker. Transduction efficiencies were similar for all constructs and consistently above 40%. The efficiency of the knockdown was verified by Western blot of cell lysates obtained 4 days (U937 cells) or 10 days (primary cells) after sorting, with a primary DEK antibody (BD Transduction Laboratories, San Jose, CA, USA). The raw data from the gene expression analysis is available through the Gene Expression Omnibus data repository, with the accession number “GSE60734”.
Gene expression microarray
RNA was isolated with the RNeasy Mini Kit (Qiagen, Hilden, Germany) from cells harvested 4 days (U937) or 10 days (primary cells) after sorting. Microarray analysis was performed in triplicates with the HumanHT-12 v4 Expression BeadChip (Illumina, San Diego, CA, USA) by the Swegene Centre for Integrative Biology at Lund University (SCIBLU). Designated as upregulated or downregulated were the genes found to be among the thousand most strongly upregulated or downregulated based on either the average fold change or the combined p value from statistical testing of the two shRNA constructs by the student’s t test. Subsequently, the number of genes to which DEK binds within 1000 bp from the transcription start site was calculated for each category. The gene expression microarray was validated by quantitative real-time PCR analysis of two genes found to be upregulated (CSF2RA; fold change 1.3, p = 0.004 and CSF3R; fold change 1.3, p = 0.04) and two genes found to be downregulated (CHMP2B; fold change −1.3, p = 0.03 and ICAM2; fold change −1.4, p = 0.002) upon knockdown of DEK in the U937 cell line. For this analysis, RNA was reverse-transcribed to cDNA with the High Capacity cDNA Reverse Transcription Kit (Life Technologies) and real-time PCR was performed using the TaqMan Gene Expression Assay (Life Technologies) and the StepOne Plus Real-Time PCR System (Life Technologies).
Gene ontology analysis
Gene ontology analysis of the genes bound by DEK was performed with the GO::TermFinder software , using gene ontology associations based on the UniProt reference proteome. The analysis was performed on the genes to which DEK binds within 1000 bp from the transcription start site, with the default p value threshold of 0.01. Fold enrichment was calculated as the percentage of the DEK-bound genes associated with a certain term divided by the percentage of the total genome associated with the same term. The result was filtered for redundant terms and terms containing more than 5000 genes. Gene ontology analysis of the genes deregulated by the knockdown of DEK was performed by Gene Set Enrichment Analysis (GSEA), using a p value threshold of 0.01 and a false discovery rate threshold of 0.05 .
Motif analysis was performed with the Discriminative Regular Expression Motif Elicitation (DREME) software , using as input the sequences from 150 bp upstream to 150 bp downstream of the middle of all DEK peaks. The p value threshold was set to 0.01. Identified motifs were subsequently matched with known motifs using the TOMTOM software  with a false discovery rate threshold of 5%.
The genome-wide AML network of gene expression was constructed by LASSO regression modeling of gene expression correlations in 3013 samples obtained by merging samples from studies based on the Affymetrix HG-U133 Plus 2.0 GeneChips (GPL570) platform (see Additional file 8 Methods for a complete list of datasets). The MILE network was constructed in the same manner but instead based on the results from stage one of the Microarray Innovations in Leukemia study . To reduce the false discovery rate, the correlation threshold of the network models was set to a level at which they did not find any correlations in randomized data. The list of transcription factors used in the analysis was manually curated after its original development as part of the Differentiation Map project .
This work was supported by grants from the Medical Faculty at Lund University (ALF) (U.G. and B.N.), the Swedish Childhood Cancer Foundation (U.G. and B.N.), the Swedish Cancer Society (U.G.), the Swedish Research Council (U.G.), the Alfred Österlund Foundation (U.G.), the Swedish Foundation for Strategic Research (B.N.), Marianne and Marcus Wallenberg’s Foundation (B.N.), Harald Jeansson’s Foundation (B.N.), the Swedish Society of Medicine (B.N.), the Siv-Inger and Per-Erik Andersson Memorial Fund (C.S.) and the Åke Olsson Foundation for Hematology (A.L.).
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