YAP/TAZ are nuclear effectors of the Hippo pathway regulating organ growth and tumorigenesis. Yet, their function as transcriptional regulators remains underinvestigated. By ChIP-seq analyses in breast cancer cells, we discovered that the YAP/TAZ transcriptional response is pervasively mediated by a dual element: TEAD factors, through which YAP/TAZ bind to DNA, co-occupying chromatin with activator protein-1 (AP-1, dimer of JUN and FOS proteins) at composite cis-regulatory elements harbouring both TEAD and AP-1 motifs. YAP/TAZ/TEAD and AP-1 form a complex that synergistically activates target genes directly involved in the control of S-phase entry and mitosis. This control occurs almost exclusively from distal enhancers that contact target promoters through chromatin looping. YAP/TAZ-induced oncogenic growth is strongly enhanced by gain of AP-1 and severely blunted by its loss. Conversely, AP-1-promoted skin tumorigenesis is prevented in YAP/TAZ conditional knockout mice. This work highlights a new layer of signalling integration, feeding on YAP/TAZ function at the chromatin level.

Cancer cells rely on dysregulated gene expression. This establishes specific transcriptional addictions that may be therapeutically exploited. Yet, the mechanisms that are ultimately responsible for these addictions are poorly understood. Here, we investigated the transcriptional dependencies of transformed cells to the transcription factors YAP and TAZ. YAP/TAZ physically engage the general coactivator bromodomain-containing protein 4 (BRD4), dictating the genome-wide association of BRD4 to chromatin. YAP/TAZ flag a large set of enhancers with super-enhancer-like functional properties. YAP/TAZ-bound enhancers mediate the recruitment of BRD4 and RNA polymerase II at YAP/TAZ-regulated promoters, boosting the expression of a host of growth-regulating genes. Treatment with small-molecule inhibitors of BRD4 blunts YAP/TAZ pro-tumorigenic activity in several cell or tissue contexts, causes the regression of pre-established, YAP/TAZ-addicted neoplastic lesions and reverts drug resistance. This work sheds light on essential mediators, mechanisms and genome-wide regulatory elements that are responsible for transcriptional addiction in cancer and lays the groundwork for a rational use of BET inhibitors according to YAP/TAZ biology.

In spring 2022, Europe faced an unprecedented heatwave, increasing the risk of West Nile virus (WNV) outbreaks. As early as 7 June 2022, WNV was detected in Culex mosquitoes in northern Italy, and – in the following days – in two blood donors, a patient with encephalitis, wild birds and additional mosquito pools. Genome sequencing demonstrated co-circulation of WNV lineage 2 and a newly introduced WNV lineage 1, which was discovered in the region in 2021.

Despite the reported increase in SARS-CoV-2-infected pets, the description of the clinical features from natural infection and the medical follow up in symptomatic pets is still not sufficiently documented. This study reports the case of an indoor cat that displayed respiratory signs and a gastrointestinal syndrome, following the COVID-19 diagnosis of his owners. Thoracic radiographies were suggestive of bronchial pneumonia, while blood tests were indicative of a mild inflammatory process. Nasal and oropharyngeal swabs tested positive through RT-qPCR assays targeting SARS-CoV-2 genes 14 days after his owners tested positive for the virus. Nasal swabs persisted to be RT-qPCR positive after 31 days. Serology confirmed the presence of antibodies through ELISA, electrochemiluminescence analysis and plaque reduction neutralization test, recording a high antibody titre after 31 days. The cat improved after medical treatment and clinically recovered. This study suggests that exposure to SARS-CoV-2 could lead to a natural infection with bronchial pneumonia in cats along with a possible prolonged persistence of SARS-CoV-2 RNA in the upper airways, albeit at a low level. The cat developed neutralizing antibodies, reaching a high titre after 31 days. Further descriptions of SARS-CoV-2 naturally infected pets, their medical management and diagnostic findings would be useful to enhance knowledge about COVID-19 in susceptible animals.

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