Highlights d Cohesin variants have distinct effects on mESC chromatin architecture and transcription d Cohesin-SA1 preferentially contributes to TAD boundary strength d Cohesin-SA2 facilitates Polycomb domain compaction through PRC1 recruitment d Cohesin-SA1 impedes and cohesin-SA2 promotes aggregation of distal Polycomb domains

Highlights d Combined Egfr/Raf1 ablation results in complete regression of a subset of PDACs d Mouse mutant Kras/Trp53-induced PDACs display distinct transcriptional profiles d PDAC transcriptional profiles determine their response to Egfr/Raf1 ablation d EGFR/c-RAF inhibition also prevents proliferation of PDXderived tumor cells

It is critical to identify biomarkers and functional networks associated with aggressive thyroid cancer to anticipate disease progression and facilitate personalized patient management. We performed miRNome sequencing of 46 thyroid tumors enriched with advanced disease patients with a median follow‐up of 96 months. MiRNome profiles correlated with tumor‐specific histopathological and molecular features, such as stromal cell infiltration and tumor driver mutation. Differential expression analysis revealed a consistent hsa‐miR‐139‐5p downexpression in primary carcinomas from patients with recurrent/metastatic disease compared to disease‐free patients, sustained in paired local metastases and validated in publicly available thyroid cancer series. Exogenous expression of hsa‐miR‐139‐5p significantly reduced migration and proliferation of anaplastic thyroid cancer cells. Proteomic analysis indicated RICTOR, SMAD2/3 and HNRNPF as putative hsa‐miR‐139‐5p targets in our cell system. Abundance of HNRNPF mRNA, encoding an alternative splicing factor involved in cryptic exon inclusion/exclusion, inversely correlated with hsa‐miR‐139‐5p expression in human tumors. RNA sequencing analysis revealed 174 splicing events differentially regulated upon HNRNPF repression in our cell system, affecting genes involved in RTK/RAS/MAPK and PI3K/AKT/MTOR signaling cascades among others. These results point at the hsa‐miR‐139‐5p/HNRNPF axis as a novel regulatory mechanism associated with the modulation of major thyroid cancer signaling pathways and tumor virulence.

Psoriasis is a common inflammatory skin disease involving a cross‐talk between epidermal and immune cells. The role of specific epidermal stem cell populations, including hair follicle stem cells (HF‐SCs) in psoriasis is not well defined. Here, we show reduced expression of c‐JUN and JUNB in bulge HF‐SCs in patients with scalp psoriasis. Using lineage tracing in mouse models of skin inflammation with inducible deletion of c‐Jun and JunB, we found that mutant bulge HF‐SCs initiate epidermal hyperplasia and skin inflammation. Mechanistically, thymic stromal lymphopoietin (TSLP) was identified in mutant cells as a paracrine factor stimulating proliferation of neighboring non‐mutant epidermal cells, while mutant inter‐follicular epidermal (IFE) cells are lost over time. Blocking TSLP in psoriasis‐like mice reduced skin inflammation and decreased epidermal proliferation, VEGFα expression, and STAT5 activation. These findings unravel distinct roles of HF‐SCs and IFE cells in inflammatory skin disease and provide novel mechanistic insights into epidermal cell interactions in inflammation.

Motivation Drug immunomodulation modifies the response of the immune system and can be therapeutically exploited in pathologies such as cancer and autoimmune diseases. Results DREIMT is a new hypothesis-generation web tool which performs drug prioritization analysis for immunomodulation. DREIMT provides significant immunomodulatory drugs targeting up to 70 immune cells subtypes through a curated database that integrates 4,960 drug profiles and ∼2,6K immune gene expression signatures. The tool also suggests potential immunomodulatory drugs targeting user-supplied gene expression signatures. Final output includes drug-signature association scores, FDRs and downloadable plots and results tables. Availability http://www.dreimt.org Supplementary information Supplementary data are available at Bioinformatics online.