A large-scale cancer-specific protein-DNA interaction network.

Cancer development and progression are generally associated with gene dysregulation, often resulting from changes in the transcription factor (TF) sequence or expression. Identifying key TFs involved in cancer gene regulation provides a framework for potential new therapeutics. This study presents a large-scale cancer gene TF-DNA interaction network, as well as an extensive promoter clone resource for future studies.

Semi-Automatic Detection of Errors in Genome-Scale Metabolic Models.

Background: Genome-Scale Metabolic Models (GSMMs) are used for numerous tasks requiring computational estimates of metabolic fluxes, from predicting novel drug targets to engineering microbes to produce valuable compounds. A key limiting step in most applications of GSMMs is ensuring their representation of the target organism's metabolism is complete and accurate. Identifying and visualizing errors in GSMMs is complicated by the fact that they contain thousands of densely interconnected reactions.

Viral cis-regulatory elements as sensors of cellular states and environmental cues.

To withstand a hostile cellular environment and replicate, viruses must sense, interpret, and respond to many internal and external cues. Retroviruses and DNA viruses can intercept these cues impinging on host transcription factors via cis-regulatory elements (CREs) in viral genomes, allowing them to sense and coordinate context-specific responses to varied signals. Here, we explore the characteristics of viral CREs, the classes of signals and host transcription factors that regulate them, and how this informs outcomes of viral replication, immune evasion, and latency.

Widespread variation in molecular interactions and regulatory properties among transcription factor isoforms.

Most human Transcription factors (TFs) genes encode multiple protein isoforms differing in DNA binding domains, effector domains, or other protein regions. The global extent to which this results in functional differences between isoforms remains unknown. Here, we systematically compared 693 isoforms of 246 TF genes, assessing DNA binding, protein binding, transcriptional activation, subcellular localization, and condensate formation.

A large-scale cancer-specific protein-DNA interaction network.

Cancer development and progression are generally associated with dysregulation of gene expression, often resulting from changes in transcription factor (TF) sequence or expression. Identifying key TFs involved in cancer gene regulation provides a framework for potential new therapeutics. This study presents a large-scale cancer gene TF-DNA interaction network as well as an extensive promoter clone resource for future studies.

Transcription factors in the development and treatment of immune disorders.

Immune function is highly controlled at the transcriptional level by the binding of transcription factors (TFs) to promoter and enhancer elements. Several TF families play major roles in immune gene expression, including NF-κB, STAT, IRF, AP-1, NRs, and NFAT, which trigger anti-pathogen responses, promote cell differentiation, and maintain immune system homeostasis. Aberrant expression, activation, or sequence of isoforms and variants of these TFs can result in autoimmune and inflammatory diseases as well as hematological and solid tumor cancers.

Paired yeast one-hybrid assays to detect DNA-binding cooperativity and antagonism across transcription factors.

Cooperativity and antagonism between transcription factors (TFs) can drastically modify their binding to regulatory DNA elements. While mapping these relationships between TFs is important for understanding their context-specific functions, existing approaches either rely on DNA binding motif predictions, interrogate one TF at a time, or study individual TFs in parallel. Here, we introduce paired yeast one-hybrid (pY1H) assays to detect cooperativity and antagonism across hundreds of TF-pairs at DNA regions of interest.

Emerging questions in transcriptional regulation.

What new questions can we ask about transcriptional regulation given recent developments in large-scale approaches?

Widespread perturbation of ETS factor binding sites in cancer.

Although >90% of somatic mutations reside in non-coding regions, few have been reported as cancer drivers. To predict driver non-coding variants (NCVs), we present a transcription factor (TF)-aware burden test based on a model of coherent TF function in promoters. We apply this test to NCVs from the Pan-Cancer Analysis of Whole Genomes cohort and predict 2555 driver NCVs in the promoters of 813 genes across 20 cancer types.

Enhanced Yeast One-Hybrid Assays to Study Protein-DNA Interactions.

The specificity in gene regulation is controlled by interactions between transcription factors (TFs) and genomic DNA regions such as promoters and enhancers. Enhanced yeast one-hybrid (eY1H) assays are among the methods used for high-throughput detection of transcription factor-DNA interactions. Here, we describe the procedure for screening interactions between DNA regions of interest ("DNA-baits") and an array of transcription factors ("TF-preys"), after DNA-bait and TF-prey yeast strains have been generated.

Epitope-Evaluator: An interactive web application to study predicted T-cell epitopes.

Multiple immunoinformatic tools have been developed to predict T-cell epitopes from protein amino acid sequences for different major histocompatibility complex (MHC) alleles. These prediction tools output hundreds of potential peptide candidates which require further processing; however, these tools are either not graphical or not friendly for non-programming users. We present Epitope-Evaluator, a web tool developed in the Shiny/R framework to interactively analyze predicted T-cell epitopes.

Intragenic proviral elements support transcription of defective HIV-1 proviruses.

HIV-1 establishes a persistent proviral reservoir by integrating into the genome of infected host cells. Current antiretroviral treatments do not target this persistent population of proviruses which include latently infected cells that upon treatment interruption can be reactivated to contribute to HIV-1 rebound. Deep sequencing of persistent HIV proviruses has revealed that greater than 90% of integrated HIV genomes are defective and unable to produce infectious virions.

Compendium of human transcription factor effector domains.

Transcription factors (TFs) regulate gene expression by binding to DNA sequences and modulating transcriptional activity through their effector domains. Despite the central role of effector domains in TF function, there is a current lack of a comprehensive resource and characterization of effector domains. Here, we provide a catalog of 924 effector domains across 594 human TFs.

Essential role of a ThPOK autoregulatory loop in the maintenance of mature CD4 T cell identity and function.

The transcription factor ThPOK (encoded by the Zbtb7b gene) controls homeostasis and differentiation of mature helper T cells, while opposing their differentiation to CD4 intraepithelial lymphocytes (IELs) in the intestinal mucosa. Thus CD4 IEL differentiation requires ThPOK transcriptional repression via reactivation of the ThPOK transcriptional silencer element (Sil). In the present study, we describe a new autoregulatory loop whereby ThPOK binds to the Sil to maintain its own long-term expression in CD4 T cells.

Therapeutic Targeting of Transcription Factors to Control the Cytokine Release Syndrome in COVID-19.

Treatment of the cytokine release syndrome (CRS) has become an important part of rescuing hospitalized COVID-19 patients. Here, we systematically explored the transcriptional regulators of inflammatory cytokines involved in the COVID-19 CRS to identify candidate transcription factors (TFs) for therapeutic targeting using approved drugs. We integrated a resource of TF-cytokine gene interactions with single-cell RNA-seq expression data from bronchoalveolar lavage fluid cells of COVID-19 patients.

Genome-wide characterization of human minisatellite VNTRs: population-specific alleles and gene expression differences.

Variable Number Tandem Repeats (VNTRs) are tandem repeat (TR) loci that vary in copy number across a population. Using our program, VNTRseek, we analyzed human whole genome sequencing datasets from 2770 individuals in order to detect minisatellite VNTRs, i.e.

A functional screen identifies transcriptional networks that regulate HIV-1 and HIV-2.

The molecular networks involved in the regulation of HIV replication, transcription, and latency remain incompletely defined. To expand our understanding of these networks, we performed an unbiased high-throughput yeast one-hybrid screen, which identified 42 human transcription factors and 85 total protein-DNA interactions with HIV-1 and HIV-2 long terminal repeats. We investigated a subset of these transcription factors for transcriptional activity in cell-based models of infection.

Comprehensive mapping of the human cytokine gene regulatory network.

Proper cytokine gene expression is essential in development, homeostasis and immune responses. Studies on the transcriptional control of cytokine genes have mostly focused on highly researched transcription factors (TFs) and cytokines, resulting in an incomplete portrait of cytokine gene regulation. Here, we used enhanced yeast one-hybrid (eY1H) assays to derive a comprehensive network comprising 1380 interactions between 265 TFs and 108 cytokine gene promoters.

Prediction of genome-wide effects of single nucleotide variants on transcription factor binding.

Single nucleotide variants (SNVs) located in transcriptional regulatory regions can result in gene expression changes that lead to adaptive or detrimental phenotypic outcomes. Here, we predict gain or loss of binding sites for 741 transcription factors (TFs) across the human genome. We calculated 'gainability' and 'disruptability' scores for each TF that represent the likelihood of binding sites being created or disrupted, respectively.

Human Virus Transcriptional Regulators.

Viral genomes encode transcriptional regulators that alter the expression of viral and host genes. Despite an emerging role in human diseases, a thorough annotation of human viral transcriptional regulators (vTRs) is currently lacking, limiting our understanding of their molecular features and functions. Here, we provide a comprehensive catalog of 419 vTRs belonging to 20 different virus families.

Discovering human transcription factor physical interactions with genetic variants, novel DNA motifs, and repetitive elements using enhanced yeast one-hybrid assays.

Identifying transcription factor (TF) binding to noncoding variants, uncharacterized DNA motifs, and repetitive genomic elements has been technically and computationally challenging. Current experimental methods, such as chromatin immunoprecipitation, generally test one TF at a time, and computational motif algorithms often lead to false-positive and -negative predictions. To address these limitations, we developed an experimental approach based on enhanced yeast one-hybrid assays.

Functional Conservation of a Developmental Switch in Mammals since the Jurassic Age.

ThPOK is a "master regulator" of T lymphocyte lineage choice, whose presence or absence is sufficient to dictate development to the CD4 or CD8 lineages, respectively. Induction of ThPOK is transcriptionally regulated, via a lineage-specific silencer element, SilThPOK. Here, we take advantage of the available genome sequence data as well as site-specific gene targeting technology, to evaluate the functional conservation of ThPOK regulation across mammalian evolution, and assess the importance of motif grammar (order and orientation of TF binding sites) on SilThPOK function in vivo.