Coronavirus Disease-2019 (COVID-19) is an infectious disease caused by the SARS-CoV-2 virus. Various studies exist about the molecular mechanisms of viral infection. However, such information is spread across many publications and it is very time-consuming to integrate, and exploit. We develop CoVex, an interactive online platform for SARS-CoV-2 host interactome exploration and drug (target) identification. CoVex integrates virus-human protein interactions, human protein-protein interactions, and drug-target interactions. It allows visual exploration of the virus-host interactome and implements systems medicine algorithms for network-based prediction of drug candidates. Thus, CoVex is a resource to understand molecular mechanisms of pathogenicity and to prioritize candidate therapeutics. We investigate recent hypotheses on a systems biology level to explore mechanistic virus life cycle drivers, and to extract drug repurposing candidates. CoVex renders COVID-19 drug research systems-medicine-ready by giving the scientific community direct access to network medicine algorithms. It is available at https://exbio.wzw.tum.de/covex/.

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Traditional drug discovery faces a severe efficacy crisis. Repurposing of registered drugs provides an alternative with lower costs and faster drug development timelines. However, the data necessary for the identification of disease modules, i.e. pathways and sub-networks describing the mechanisms of complex diseases which contain potential drug targets, are scattered across independent databases. Moreover, existing studies are limited to predictions for specific diseases or non-translational algorithmic approaches. There is an unmet need for adaptable tools allowing biomedical researchers to employ network-based drug repurposing approaches for their individual use cases. We close this gap with NeDRex, an integrative and interactive platform for network-based drug repurposing and disease module discovery. NeDRex integrates ten different data sources covering genes, drugs, drug targets, disease annotations, and their relationships. NeDRex allows for constructing heterogeneous biological networks, mining them for disease modules, prioritizing drugs targeting disease mechanisms, and statistical validation. We demonstrate the utility of NeDRex in five specific use-cases.

Architectural proteins are essential epigenetic regulators that play a critical role in organizing chromatin and controlling gene expression. CTCF (CCCTC-binding factor) is a key architectural protein responsible for maintaining the intricate 3D structure of chromatin. Because of its multivalent properties and plasticity to bind various sequences, CTCF is similar to a Swiss knife for genome organization. Despite the importance of this protein, its mechanisms of action are not fully elucidated. It has been hypothesized that its versatility is achieved through interaction with multiple partners, forming a complex network that regulates chromatin folding within the nucleus. In this review, we delve into CTCF’s interactions with other molecules involved in epigenetic processes, particularly histone and DNA demethylases, as well as several long non-coding RNAs (lncRNAs) that are able to recruit CTCF. Our review highlights the importance of CTCF partners to shed light on chromatin regulation and pave the way for future exploration of the mechanisms that enable the finely-tuned role of CTCF as a master regulator of chromatin.

Radioresistance of tumor cells gives rise to local recurrence and disease progression in many patients. MicroRNAs (miRNAs) are master regulators of gene expression that control oncogenic pathways to modulate the radiotherapy response of cells. In the present study, differential expression profiling assays identified 16 deregulated miRNAs in acquired radioresistant breast cancer cells, of which miR‐122 was observed to be up‐regulated. Functional analysis revealed that miR‐122 has a role as a tumor suppressor in parental cells by decreasing survival and promoting radiosensitivity. However, in radioresistant cells, miR‐122 functions as an oncomiR by promoting survival. The transcriptomic landscape resulting from knockdown of miR‐122 in radioresistant cells showed modulation of the ZNF611 , ZNF304 , RIPK1 , HRAS , DUSP8 and TNFRSF21 genes. Moreover, miR‐122 and the set of affected genes were prognostic factors in breast cancer patients treated with radiotherapy. Our data indicate that up‐regulation of miR‐122 promotes cell survival in acquired radioresistant breast cancer and also suggest that miR‐122 differentially controls the response to radiotherapy by a dual function as a tumor suppressor an and oncomiR dependent on cell phenotype.

COVID-19 is an infection caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome coronavirus 2), which has caused a global outbreak. Current research efforts are focused on the understanding of the molecular mechanisms involved in SARS-CoV-2 infection in order to propose drug-based therapeutic options. Transcriptional changes due to epigenetic regulation are key host cell responses to viral infection and have been studied in SARS-CoV and MERS-CoV; however, such changes are not fully described for SARS-CoV-2. In this study, we analyzed multiple transcriptomes obtained from cell lines infected with MERS-CoV, SARS-CoV, and SARS-CoV-2, and from COVID-19 patient-derived samples. Using integrative analyses of gene co-expression networks and de-novo pathway enrichment, we characterize different gene modules and protein pathways enriched with Transcription Factors or Epifactors relevant for SARS-CoV-2 infection. We identified EP300, MOV10, RELA, and TRIM25 as top candidates, and more than 60 additional proteins involved in the epigenetic response during viral infection that has therapeutic potential. Our results show that targeting the epigenetic machinery could be a feasible alternative to treat COVID-19.

The identification of prognostic biomarkers is a priority for patients suffering from high-grade serous ovarian cancer (SOC), which accounts for >70% of ovarian cancer (OC) deaths. Meanwhile, borderline ovarian cancer (BOC) is a low malignancy tumor and usually patients undergo surgery with low probabilities of recurrence. However, SOC remains the most lethal neoplasm due to the lack of biomarkers for early diagnosis and prognosis. In this regard, BORIS ( CTCFL ), a CTCF paralog, is a promising cancer biomarker that is overexpressed and controls transcription in several cancer types, mainly in OC. Studies suggest that BORIS has an important function in OC by altering gene expression, but the effect and extent to which BORIS influences transcription in OC from a genome-wide perspective is unclear. Here, we sought to identify BORIS target genes in an OC cell line (OVCAR3) with potential biomarker use in OC tumor samples. To achieve this, we performed in vitro knockout and knockdown experiments of BORIS in OVCAR3 cell line followed by expression microarrays and bioinformatics network enrichment analysis to identify relevant BORIS target genes. In addition, ex vivo expression data analysis of 373 ovarian cancer patients were evaluated to identify the expression patterns of BORIS target genes. In vitro, we uncovered 130 differentially expressed genes and obtained the BORIS-associated regulatory network, in which the androgen receptor (AR) acts as a major transcription factor. Also, FN1 , FAM129A , and CD97 genes, which are related to chemoresistance and metastases in OC, were identified. In SOC patients, we observed that malignancy is associated with high levels of BORIS expression while BOC patients show lower levels. Our study suggests that BORIS acts as a main regulator, and has the potential to be used as a prognostic biomarker and to yield novel drug targets among the genes BORIS controls in SOC patients.

Angiogenesis is a crucial process for organ morphogenesis and growth during development, and it is especially relevant during the repair of wounded tissue in adults. It is coordinated by an equilibrium of pro- and anti-angiogenic factors; nevertheless, when affected, it promotes several diseases. Lately, a growing body of evidence is indicating that non-coding RNAs (ncRNAs), such as miRNAs, circRNAs, and lncRNAs, play critical roles in angiogenesis. These ncRNAs can act in cis or trans and alter gene transcription by several mechanisms including epigenetic processes. In the following pages, we will discuss the functions of ncRNAs in the regulation of angiogenesis and neovascularization, both in normal and disease contexts, from an epigenetic perspective. Additionally, we will describe the contribution of Next-Generation Sequencing (NGS) techniques to the discovery and understanding of the role of ncRNAs in angiogenesis.