SV-plaudit is a framework for rapidly curating structural variant (SV) predictions. For each SV, we generate an image that visualizes the coverage and alignment signals from a set of samples. Images are uploaded to our cloud framework where users assess the quality of each image using a client-side web application. Reports can then be generated as a tab-delimited file or annotated Variant Call Format (VCF) file. As a proof of principle, nine researchers collaborated for 1 hour to evaluate 1,350 SVs each. We anticipate that SV-plaudit will become a standard step in variant calling pipelines and the crowd-sourced curation of other biological results.Code available at https://github.com/jbelyeu/SV-plauditDemonstration video available at https://www.youtube.com/watch?v=ono8kHMKxDs

Breast cancers are divided into subtypes with different prognoses and treatment responses based on global differences in gene expression. Luminal breast cancer gene expression and proliferation are driven by Estrogen Receptor alpha and targeting this transcription factor is the most effective therapy for this subtype. By contrast, it remains unclear which transcription factors drive the gene expression signature that defines basallike triple-negative breast cancer and there are no targeted therapies approved to treat this aggressive subtype. In this study, we utilized integrated genomic analysis of DNA methylation, chromatin accessibility, transcription factor binding, and gene expression in large collections of breast cancer cell lines and patient tumors to identify transcription factors responsible for the basal-like gene expression program. Glucocorticoid receptor (GR) and signal transducer and activator of transcription 3 (STAT3) bind to the same genomic regulatory regions, which were specifically open and unmethylated in basal-like breast cancer. These transcription factors cooperated to regulate expression of hundreds of genes in the basal-like gene expression signature which were associated with poor prognosis. Combination treatment with small molecule inhibitors of both transcription factors resulted in synergistic decreases in cell growth in cell lines and patient-derived organoid models. This study demonstrates that GR and STAT3 cooperate to regulate the basal-like breast cancer gene expression program and provides the basis for improved therapy for basal-like triplenegative breast cancer through rational combination of STAT3 and GR inhibitors. Significance This study demonstrates that GR and STAT3 cooperate to activate the canonical gene expression signature of basal-like TNBC and that combination treatment with STAT3 and GR inhibitors could provide synergistic therapeutic efficacy. Research.

Cultivated blueberry (Vaccinium corymbosum, Vaccinium angustifolium, Vaccinium darrowii, and Vaccinium virgatum) is an economically important fruit crop native to North America and a member of the Ericaceae family. Several species in the Ericaceae family including cranberry, lignonberry, bilberry, and neotropical blueberry species have been shown to produce iridoids, a class of pharmacologically important compounds present in over 15 plant families demonstrated to have a wide range of biological activities in humans including anti-cancer, anti-bacterial, and anti-inflammatory. While the antioxidant capacity of cultivated blueberry has been well studied, surveys of iridoid production in blueberry have been restricted to fruit of a very limited number of accessions of V. corymbosum, V. angustifolium and V. virgatum; none of these analyses have detected iridoids. To provide a broader survey of iridoid biosynthesis in cultivated blueberry, we constructed a panel of 84 accessions representing a wide range of cultivated market classes, as well as wild blueberry species, and surveyed these for the presence of iridoids. We identified the iridoid glycoside monotropein in fruits and leaves of all 13 wild Vaccinium species, yet only five of the 71 cultivars. Monotropein positive cultivars all had recent introgressions from wild species, suggesting that iridoid production can be targeted through breeding efforts that incorporate wild germplasm. A series of diverse developmental tissues was also surveyed in the diversity panel, demonstrating a wide range in iridoid content across tissues. Taken together, this data provides the foundation to dissect the molecular and genetic basis of iridoid production in blueberry.

c-Myc protooncogene places a demand on glucose uptake to drive glucose-dependent biosynthetic pathways. To achieve this demand, c-Myc protein (Myc henceforth) drives the expression of glucose transporters and represses the expression of Thioredoxin Interacting Protein (TXNIP), which is a potent negative regulator of glucose uptake. A Myc high/TXNIP low gene signature is clinically significant as it correlates with poor clinical prognosis in Triple-Negative Breast Cancer (TNBC) but not in other subtypes of breast cancer. To better understand how TXNIP function contributes to the aggressive behavior of TNBC, we generated TXNIP null MDA-MB-231 (231:TKO) cells for our study. We show here that TXNIP loss drives a transcriptional program that resembles those driven by Myc and increases global Myc genome occupancy. TXNIP loss allows Myc to invade the promoters and enhancers of target genes that are potentially relevant to cell transformation. Together, these findings suggest that TXNIP is a broad repressor of Myc genomic binding. The increase in Myc genomic binding in the 231:TKO cells expands the Myc-dependent transcriptome we identified in parental MDA-MB-231 cells. This expansion of Myc-dependent transcription following TXNIP loss occurs without an apparent increase in Myc’s intrinsic capacity to activate transcription and without increasing Myc levels. Together, our findings suggest that TXNIP loss mimics Myc overexpression, connecting Myc genomic binding and transcriptional programs to the metabolic signals that control TXNIP expression.