Biology subjects

Singer, B. D.

Publications and source records attributed to Singer, B. D..

At least 19 recordsLinked to original sources

bioRxiv2026

Maintenance DNA methylation is necessary for age-related alterations in regulatory T cell transcriptional and DNA methylation signatures

CD4+FOXP3+ regulatory T (Treg) cells maintain self-tolerance, restrain immune responses during inflammatory stimuli, and promote tissue function and repair. Treg cell lineage identity, stability, and function depend on specific DNA methylation patterns maintained by the epigenetic regulator, UHRF1. Aging disrupts DNA methylation patterns necessary for Treg cell-mediated lung repair in a cell-autonomous manner. Nevertheless, whether maintenance DNA methylation is necessary for age-related Treg cell transcriptional and methylation programs is unknown. Here, we performed transcriptional and DNA methylation profiling on young and old Treg cells isolated from mice with chimeric Treg cell-specific loss of UHRF1. We observed cell-autonomous, age-related alterations in transcriptional and DNA methylation signatures that were dependent on UHRF1. We conclude that maintenance DNA methylation is required for age-related alterations in Treg cell transcriptional and DNA methylation signatures.

immunology↗

bioRxiv2026

Pathogen-specific host responses define distinct pneumonia endotypes in the human lung

Pneumonia is the leading cause of death from infectious disease worldwide. The diagnosis and treatment of patients with pneumonia lag behind other major conditions, relying on syndromic definitions that lack molecular resolution and ignore underlying endotypes. We sought to test the hypothesis that dynamic pathogen-specific host responses in the alveolar space represent distinct pneumonia endotypes linked to different clinical features and outcomes. We prospectively enrolled a cohort of 690 patients (including immunocompromised patients) with known or suspected pneumonia receiving mechanical ventilation in whom the etiology of pneumonia was determined by gold-standard analysis of distal lung fluid obtained by bronchoalveolar lavage (BAL) combined with clinical adjudication. From these patients, we analyzed 792 BAL fluid samples, including 310 serial samples, using flow cytometry (482 patients) and single-cell RNA-sequencing (170 patients; 263 samples, complemented by 9 healthy controls and 25 post-COVID-19 patients, yielding [~]2.4 million single cells across 28 cell types), and extracted daily clinical data from the electronic health record (>15,000 patient-days). We used machine learning models to identify pathogen-specific host responses in the transcriptome of alveolar immune cells that were associated with changes in alveolar cell abundance and clinical features. Our results suggest that therapeutic strategies for pneumonia should be individualized to specific host-pathogen interactions.

immunology↗

bioRxiv2025

Umbilical Cord Blood Cell Transcriptional and Methylation Signatures at Birth Are Associated with BPD Development.

Bronchopulmonary dysplasia (BPD) is the most common respiratory disease in preterm infants born at less than 28 weeks gestation. Most existing clinical prediction models for BPD show limited accuracy in predicting BPD development when validated using external data, stressing the need for novel biomarkers to identify at-risk infants for early and effective interventions. We leveraged existing frozen umbilical cord blood samples from the Northwestern University Cord Blood Biobank (NUCord) to perform parallel transcriptional and DNA methylation profiling. BPD-associated differentially expressed genes (DEGs) in our cohort included markers previously established in clinical and animal BPD studies, such as genes related to NF-{kappa}B signaling and immune responses. We also identified that BPD development is associated with disrupted methylation signatures in microRNA genes and genes associated with glucose metabolism. Our results suggest that BPD development is associated with distinct transcriptomic and epigenetic signatures when compared with healthy term and preterm infants. These signatures may represent biomarkers measurable at birth that predict BPD development during a time window when preventative or therapeutic interventions could be applied.

genomics↗

bioRxiv2025

Maintenance DNA methylation is required for induced regulatory T cell reparative function following viral pneumonia

FOXP3+ natural regulatory T cells (nTregs) promote resolution of inflammation and repair of epithelial damage following viral pneumonia-induced lung injury, thus representing a cellular therapy for patients with acute respiratory distress syndrome (ARDS). Whether in vitro induced Tregs (iTregs), which can be rapidly generated in substantial numbers from conventional T cells, also promote lung recovery is unknown. nTregs require specific DNA methylation patterns maintained by the epigenetic regulator, ubiquitin-like with PHD and RING finger domains 1 (UHRF1). Here, we tested whether iTregs promote recovery following viral pneumonia and whether iTregs require UHRF1 for their pro-recovery function. We found that adoptive transfer of iTregs to mice with influenza virus pneumonia promotes lung recovery and that loss of UHRF1-mediated maintenance DNA methylation in iTregs leads to reduced engraftment and a delayed repair response. Transcriptional and DNA methylation profiling of adoptively transferred UHRF1-deficient iTregs that had trafficked to influenza-injured lungs demonstrated transcriptional instability with gain of effector T cell lineage-defining transcription factors. Strategies to promote the stability of iTregs could be leveraged to further augment their pro-recovery function during viral pneumonia and other causes of ARDS.

immunology↗

bioRxiv2025

Distinct Control of histone H1 expression within the Histone Locus body by CRAMP1

Proper histone gene expression is critical to cell viability and maintaining genomic integrity. Multiple histone genes organized into three genomic loci encode for replication coupled core and linker histones. Histone gene expression and transcript processing is orchestrated in the histone locus body (HLB) within the nucleus. We identified human CRAMP1 as a selective regulator of linker histone H1 expression. CRAMP1 is recruited to the HLB in RPE1hTERT cells. Affinity purification shows that CRAMP1 physically associates the HLB component GON4L (a.k.a. YARP). We show that the PAH domains of GON4L interact with CRAMP1. CRAMP1 disruption results in a loss of histone H1 expression and a reduction in H1 protein. CRAMP1 occupies the unmethylated promoters of the replication coupled linker histone genes that reside within the histone locus body, and the replication independent histone H1 loci, which reside in a region of the genome without other histone genes. Together these data identify CRAMP1 as a novel and selective regulator of histone H1 gene expression.

genomics↗

bioRxiv2024

FOXP3+ Regulatory T Cells Require TBET to Regulate Activated CD8+ T Cells During Recovery from Influenza Infection

FOXP3+ regulatory T (Treg) cells are necessary to coordinate resolution of lung inflammation and a return to homeostasis after respiratory viral infections, but the specific molecular requirements for these functions and the cell types governed by Treg cells remain unclear. This question holds significance as clinical trials of Treg cell transfer therapy for respiratory viral infection are being planned and executed. Here, we report causal experiments in mice determining that Treg cells are necessary to control the numbers of activated CD8+ T cells during recovery from influenza infection. Using a genetic strategy paired with adoptive transfer techniques, we determined that Treg cells require the transcription factor TBET to regulate these potentially pro-inflammatory CD8+ T cells. Surprisingly, we found that Treg cells are dispensable for the generation of CD8+ lung tissue resident-memory T (Trm) cells yet similarly influence the transcriptional programming of CD8+ Trm and activated T cells. Our study highlights the role of Treg cells in regulating the CD8+ T cell response during recovery from influenza infection.

immunology↗

bioRxiv2024

Novel enzyme-based reduced representation method for DNA methylation profiling with low inputs

DNA methylation at cytosine-phospho-guanine (CpG) residues is a vital biological process that regulates cell identity and function. Although widely used, bisulfite-based cytosine conversion procedures for DNA methylation sequencing require high temperature and extreme pH, which lead to DNA degradation, especially among unmethylated cytosines. Enzymatic methylation sequencing (EM-seq), an enzyme-based cytosine conversion method, has been proposed as a less biased alternative for methylation profiling. Compared to bisulfite-based methods, EM-seq boasts greater genome coverage with less GC bias and has the potential to cover more CpGs with the same number of reads (i.e., higher signal-to-noise ratio). Reduced representation approaches enrich samples for CpG-rich genomic regions, thereby enhancing throughput and cost effectiveness. We hypothesized that enzyme-based technology could be adapted for reduced representation methylation sequencing to enable high-resolution DNA methylation profiling on low-input samples, including those obtained from clinical specimens. We leveraged the well-established differences in methylation profile between mouse CD4+ T cell populations to compare the performance of a novel reduced representation EM-seq (RREM-seq) procedure against an established reduced representation bisulfite sequencing (RRBS) protocol. While the RRBS method failed to generate reliable DNA libraries when using <2 ng of DNA (equivalent to DNA from around 350 cells), the RREM-seq method successfully generated reliable DNA libraries from 1-25 ng of mouse and human DNA. Ultra-low-input (<2-ng) RREM-seq libraries final concentration, regulatory genomic element coverage, and methylation status within lineage-defining Treg cell-specific super-enhancers were comparable to RRBS libraries with more than 10-fold higher DNA input. RREM-seq also successfully detected lineage-defining methylation differences between alveolar Tconv and Treg cells obtained from mechanically ventilated patients with severe SARS-CoV-2 pneumonia. Our RREM-seq method enables single-nucleotide resolution methylation profiling using low-input samples, including from clinical sources.

genomics↗

bioRxiv2023

A distinctive evolution of alveolar T cell responses is associated with clinical outcomes in unvaccinated patients with SARS-CoV-2 pneumonia

Pathogen clearance and resolution of inflammation in patients with pneumonia require an effective local T cell response. Nevertheless, local T cell activation may drive lung injury, particularly during prolonged episodes of respiratory failure characteristic of severe SARS-CoV-2 pneumonia. While T cell responses in the peripheral blood are well described, the evolution of T cell phenotypes and molecular signatures in the distal lung of patients with severe pneumonia caused by SARS-CoV-2 or other pathogens is understudied. Accordingly, we serially obtained 432 bronchoalveolar lavage fluid samples from 273 patients with severe pneumonia and respiratory failure, including 74 unvaccinated patients with COVID-19, and performed flow cytometry, transcriptional, and T cell receptor profiling on sorted CD8+ and CD4+ T cell subsets. In patients with COVID-19 but not pneumonia secondary to other pathogens, we found that early and persistent enrichment in CD8+ and CD4+ T cell subsets correlated with survival to hospital discharge. Activation of interferon signaling pathways early after intubation for COVID-19 was associated with favorable outcomes, while activation of NF-{kappa}B-driven programs late in disease was associated with poor outcomes. Patients with SARS-CoV-2 pneumonia whose alveolar T cells preferentially targeted the Spike and Nucleocapsid proteins tended to experience more favorable outcomes than patients whose T cells predominantly targeted the ORF1ab polyprotein complex. These results suggest that in patients with severe SARS-CoV-2 pneumonia, alveolar T cell interferon responses targeting structural SARS-CoV-2 proteins characterize patients who recover, yet these responses progress to NF-{kappa}B activation against non-structural proteins in patients who go on to experience poor clinical outcomes.

systems biology↗

bioRxiv2023

AMP-activated protein kinase is necessary for Treg cell functional adaptation to microenvironmental stress

CD4+FOXP3+ regulatory T (Treg) cells maintain self-tolerance, suppress the immune response to cancer, and protect against tissue injury in the lung and other organs. Treg cells require mitochondrial metabolism to exert their function, but how Treg cells adapt their metabolic programs to sustain and optimize their function during an immune response occurring in a metabolically stressed microenvironment remains unclear. Here, we tested whether Treg cells require the energy homeostasis-maintaining enzyme AMP-activated protein kinase (AMPK) to adapt to metabolically aberrant microenvironments caused by malignancy or lung injury, finding that AMPK is dispensable for Treg cell immune-homeostatic function but is necessary for full Treg cell function in B16 melanoma tumors and during acute lung injury caused by influenza virus pneumonia. AMPK-deficient Treg cells had lower mitochondrial mass and exhibited an impaired ability to maximize aerobic respiration. Mechanistically, we found that AMPK regulates DNA methyltransferase 1 to promote transcriptional programs associated with mitochondrial function in the tumor microenvironment. In the lung during viral pneumonia, we found that AMPK sustains metabolic homeostasis and mitochondrial activity. Induction of DNA hypomethylation was sufficient to rescue mitochondrial mass in AMPK-deficient Treg cells, linking DNA methylation with AMPK function and mitochondrial metabolism. These results define AMPK as a determinant of Treg cell adaptation to metabolic stress and offer potential therapeutic targets in cancer and tissue injury.

immunology↗

bioRxiv2023

Transcriptional profiling of peripheral blood mononuclear cells identifies inflammatory phenotypes in ataxia telangiectasia

Ataxia telangiectasia (A-T) is an autosomal recessive neurodegenerative disease with widespread systemic manifestations and marked variability in clinical phenotypes. In this study, we sought to determine whether transcriptomic profiling of peripheral blood mononuclear cells defines subsets of individuals with A-T beyond mild and classic phenotypes, enabling identification of novel features for disease classification and treatment response to therapy. MethodsParticipants with stable A-T (n=90) were recruited and compared with unaffected controls (n=15). PBMCs were isolated and bulk RNAseq was performed. Plasma was also isolated in a subset of individuals. Affected individuals were designated mild or classic based on ATM mutations and clinical and laboratory features. ResultsPeople with classic A-T were more likely to be younger and IgA deficient and to have higher alpha-fetoprotein levels and lower % forced vital capacity compared to individuals with mild A-T. In classic A-T, the expression of genes required for V(D)J recombination was lower, and the expression of genes required for inflammatory activity was higher. We assigned inflammatory scores to study participants and found that inflammatory scores were highly variable among people with classic A-T and that higher scores were associated with lower ATM mRNA levels. Using a cell type deconvolution approach, we inferred that CD4+ T cells and CD8+ T cells were lower in number in people with classic A-T. Finally, we showed that individuals with classic A-T exhibit higher SERPINE1 (PAI-1) mRNA and plasma protein levels, irrespective of age, and higher FLT4 (VEGFR3) and IL6ST (GP130) plasma protein levels compared with mild A-T and controls. ConclusionUsing an unbiased transcriptomic approach, we identified novel features and developed an inflammatory score to identify subsets of individuals with different inflammatory phenotypes in A-T. Findings from this study could be used to help direct treatment and to track treatment response to therapy.

immunology↗

bioRxiv2023

Prolonged exposure to lung-derived cytokines is associated with inflammatory activation of microglia in patients with COVID-19

Neurological impairment is the most common finding in patients with post-acute sequelae of COVID-19. Furthermore, survivors of pneumonia from any cause have an elevated risk of dementia1-4. Dysfunction in microglia, the primary immune cell in the brain, has been linked to cognitive impairment in murine models of dementia and in humans5. Here, we report a transcriptional response in human microglia collected from patients who died following COVID-19 suggestive of their activation by TNF-[a] and other circulating pro-inflammatory cytokines. Consistent with these findings, the levels of 55 alveolar and plasma cytokines were elevated in a cohort of 341 patients with respiratory failure, including 93 unvaccinated patients with COVID-19 and 203 patients with other causes of pneumonia. While peak levels of pro-inflammatory cytokines were similar in patients with pneumonia irrespective of etiology, cumulative cytokine exposure was higher in patients with COVID-19. Corticosteroid treatment, which has been shown to be beneficial in patients with COVID-196, was associated with lower levels of CXCL10, CCL8, and CCL2--molecules that sustain inflammatory circuits between alveolar macrophages harboring SARS-CoV-2 and activated T cells7. These findings suggest that corticosteroids may break this cycle and decrease systemic exposure to lung-derived cytokines and inflammatory activation of microglia in patients with COVID-19.

immunology↗

bioRxiv2022

Superiority of intranasal over systemic administration of bioengineered soluble ACE2 for survival and brain protection against SARS-CoV-2 infection

The present study was designed to investigate the effects of a soluble ACE2 protein termed ACE2 618-DDC-ABD, bioengineered to have long duration of action and high binding affinity to SARS-CoV-2, when administered either intranasally (IN) or intraperitoneally (IP) and before or after SARS-CoV-2 inoculation. K18hACE2 mice permissive for SARS-CoV-2 infection were inoculated with 2x104 PFU wildtype SARS-CoV-2. In one protocol, ACE2 618-DDC-ABD was given either IN or IP, pre- and post-viral inoculation. In a second protocol, ACE2 618-DDC-ABD was given either IN, IP or IN+IP but only post-viral inoculation. In addition, A549 and Vero E6 cells were used to test neutralization of SARS-CoV-2 variants by ACE2 618-DDC-ABD at different concentrations. Survival by day 5 was 0% in infected untreated mice, and 40% in mice from the ACE2 618-DDC-ABD IP-pre treated group. By contrast, in the IN-pre group survival was 90%, histopathology of brain and kidney was essentially normal and markedly improved in the lungs. When ACE2 618-DDC-ABD was administered only post viral inoculation, survival was 30% in the IN+IP group, 20% in the IN and 0% in the IP group. Brain SARS-CoV-2 titers were high in all groups except for the IN-pre group where titers were undetectable in all mice. In cells permissive for SARS-CoV-2 infection, ACE2 618-DDC-ABD neutralized wildtype SARS-CoV-2 at high concentrations, whereas much lower concentrations neutralized omicron BA. 1. We conclude that ACE2 618-DDC-ABD provides much better survival and organ protection when administered intranasally than when given systemically or after viral inoculation and that lowering brain titers is a critical determinant of survival and organ protection.

pathology↗

bioRxiv2022

DNA methyltransferase inhibition induces dynamic gene expression changes in lung CD4+ T cells of neonatal mice with E. coli pneumonia

IntroductionBacterial pulmonary infections are a major cause of morbidity and mortality in neonates, with less severity in older children. Previous studies demonstrated that the DNA of CD4+ T cells in the mouse lung, whose primary responsibility is to coordinate the immune response foreign pathogens, is differentially methylated in neonates compared with juveniles. Nevertheless, the effect of this differential DNA methylation on CD4+ T cell gene expression and response to infection remains unclear. MethodsWe treated E. coli-infected neonatal (4-day-old) and juvenile (13-day-old) mice with decitabine (DAC), a DNA methyltransferase inhibitor with broad-spectrum DNA demethylating activity, and performed simultaneous genome-wide DNA methylation and transcriptional profiling on lung CD4+ T cells. ResultsJuvenile and neonatal mice experienced differential demethylation in response to DAC treatment, with larger methylation differences observed in neonates. By cross-filtering differentially expressed genes between juveniles and neonates with those sites that were demethylated in neonates, we found that interferon-responsive genes such as Ifit1 are the most down-regulated methylation-sensitive genes in neonatal mice. DAC treatment shifted neonatal lung CD4+ T cells toward a gene expression program similar to that of juveniles. ConclusionFollowing lung infection with E. coli, lung CD4+ T cells in neonatal mice exhibit epigenetic repression of important host defense pathways, which are activated by inhibition of DNA methyltransferase activity to resemble a more mature profile.

immunology↗

bioRxiv2022

Cellular and molecular dynamics in the lungs of neonatal and juvenile mice in response to E. coli

Bacterial pneumonias cause significantly higher morbidity and mortality in neonates compared to other age groups. To understand the immune mechanisms that underlie these age-related differences, we employed a mouse model of E. coli pneumonia to examine cellular and molecular dynamics in immune responsiveness in neonates (PND 3-5) and juveniles (PND 12-18) at 24, 48, and 72 hours. Cytokine gene expression from whole lung extracts was quantified using qRT-PCR. E. coli challenge resulted in rapid and significant increases in neutrophils, monocytes, and y{delta}T cells and significant decreases in dendritic cells and alveolar macrophages for both neonates and juveniles. Juveniles had significant increases in interstitial macrophages and recruited monocytes that were not observed in neonatal lungs. Expression of IFN{gamma}-responsive genes were positively correlated with the levels and dynamics of MHCII-expressing innate cells in neonatal and juvenile lungs. Several facets of the responses of wild-type neonates was recapitulated in juvenile MHCII-/- juveniles. Employing a pre-clinical model of E. coli pneumonia, we identified significant differences in the early cellular and molecular dynamics in the lungs that likely contribute to the elevated susceptibility of neonates to bacterial pneumonia and could represent targets for intervention to improve respiratory outcomes and survivability of neonates.

immunology↗

bioRxiv2020

Alveolitis in severe SARS-CoV-2 pneumonia is driven by self-sustaining circuits between infected alveolar macrophages and T cells

Some patients infected with Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) develop severe pneumonia and the acute respiratory distress syndrome (ARDS) [1]. Distinct clinical features in these patients have led to speculation that the immune response to virus in the SARS-CoV-2-infected alveolus differs from other types of pneumonia [2]. We collected bronchoalveolar lavage fluid samples from 86 patients with SARS-CoV-2-induced respiratory failure and 252 patients with known or suspected pneumonia from other pathogens and subjected them to flow cytometry and bulk transcriptomic profiling. We performed single cell RNA-Seq in 5 bronchoalveolar lavage fluid samples collected from patients with severe COVID-19 within 48 hours of intubation. In the majority of patients with SARS-CoV-2 infection at the onset of mechanical ventilation, the alveolar space is persistently enriched in alveolar macrophages and T cells without neutrophilia. Bulk and single cell transcriptomic profiling suggest SARS-CoV-2 infects alveolar macrophages that respond by recruiting T cells. These T cells release interferon-gamma to induce inflammatory cytokine release from alveolar macrophages and further promote T cell recruitment. Our results suggest SARS-CoV-2 causes a slowly unfolding, spatially-limited alveolitis in which alveolar macrophages harboring SARS-CoV-2 transcripts and T cells form a positive feedback loop that drives progressive alveolar inflammation. This manuscript is accompanied by an online resource: https://www.nupulmonary.org/covid-19/ One sentence summarySARS-CoV-2-infected alveolar macrophages form positive feedback loops with T cells in patients with severe COVID-19.

immunology↗

bioRxiv2020

Aging imparts cell-autonomous dysfunction to regulatory T cells during recovery from influenza pneumonia

Regulatory T (Treg) cells orchestrate resolution and repair of acute lung inflammation and injury following viral pneumonia. Compared with younger patients, older individuals experience impaired recovery and worse clinical outcomes after severe viral infections, including influenza and the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Whether age is a key determinant of Treg cell pro-repair function following lung injury remains unknown. Here, we show that aging results in a cell-autonomous impairment of reparative Treg cell function following experimental influenza pneumonia. Transcriptional and DNA methylation profiling of sorted Treg cells provide insight into the mechanisms underlying their age-related dysfunction, with Treg cells from aged mice demonstrating both loss of reparative programs and gain of maladaptive programs. Novel strategies that restore youthful Treg cell functional programs could be leveraged as therapies to improve outcomes among older individuals with severe viral pneumonia.

immunology↗

bioRxiv2020

Maintenance DNA methylation is essential for regulatory T cell development and stability of suppressive function

Regulatory T (Treg) cells require Foxp3 expression and induction of a specific DNA hypomethylation signature during development, after which Treg cells persist as a self-renewing population that regulates immune system activation. Whether maintenance DNA methylation is required for Treg cell lineage development and stability and how methylation patterns are maintained during lineage self-renewal remain unclear. Here, we demonstrate that the epigenetic regulator Uhrf1 is essential for maintenance of methyl-DNA marks that stabilize Treg cellular identity by repressing effector T cell transcriptional programs. Constitutive and induced deficiency of Uhrf1 within Foxp3+ cells resulted in global yet non-uniform loss of DNA methylation, derepression of inflammatory transcriptional programs, destabilization of the Treg cell lineage, spontaneous inflammation, and enhanced tumor immunity. These findings support a paradigm in which maintenance DNA methylation is required in distinct regions of the Treg cell genome for both lineage establishment and stability of identity and suppressive function.

immunology↗

bioRxiv2020

Cancer-specific CTCF binding facilitates oncogenic transcriptional dysregulation

BackgroundThe 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.

genomics↗