The ETS transcription factor ETV6 constrains the transcriptional activity of EWS-FLI to promote Ewing sarcoma.

Transcription factors (TFs) are frequently mutated in cancer. Paediatric cancers exhibit few mutations genome-wide but frequently harbour sentinel mutations that affect TFs, which provides a context to precisely study the transcriptional circuits that support mutant TF-driven oncogenesis. A broadly relevant mechanism that has garnered intense focus involves the ability of mutant TFs to hijack wild-type lineage-specific TFs in self-reinforcing transcriptional circuits. However, it is not known whether this specific type of circuitry is equally crucial in all mutant TF-driven cancers. Here we describe an alternative yet central transcriptional mechanism that promotes Ewing sarcoma, wherein constraint, rather than reinforcement, of the activity of the fusion TF EWS-FLI supports cancer growth. We discover that ETV6 is a crucial TF dependency that is specific to this disease because it, counter-intuitively, represses the transcriptional output of EWS-FLI. This work discovers a previously undescribed transcriptional mechanism that promotes cancer.

Self-Perceived Food Intolerances Are Common and Associated with Clinical Severity in Childhood Irritable Bowel Syndrome.

BACKGROUND: Adults with irritable bowel syndrome (IBS) frequently identify foods as exacerbating their gastrointestinal symptoms. In children with IBS, the prevalence of perceived food intolerances and their impact are unknown. OBJECTIVE: Our aim was to determine the prevalence of self-perceived food intolerances and the relationship of these intolerances to abdominal pain, psychosocial distress, and quality of life in children with IBS. DESIGN: We conducted a cross-sectional study. Questionnaire and prospective diary data were collected from 2008 to 2014 by trained research coordinators. PARTICIPANTS/SETTING: Participants were children 7 to 18 years old (pediatric Rome III IBS, n=154; age-sex matched healthy children, n=32) in Houston, TX. MEASURES: Perceived food intolerances and avoided foods were captured using the Childhood Food and Symptom Association Questionnaire. IBS severity was assessed by a ≥7-day pain diary and validated psychosocial questionnaires assessing quality of life, somatization, functional disability, depression, and anxiety. STATISTICAL ANALYSES PERFORMED: We used descriptive Spearman bivariate correlation, χ(2), and Poisson log-linear generalized model with Wald χ(2) statistics. RESULTS: A greater proportion of children with IBS (143 of 154 [92.9%]) vs healthy children (20 of 32 [62.5%]) identified at least one self-perceived food intolerance (χ(2)=22.5; P<0.001). Children with IBS identified a greater number (median=4 [25% to 75% quartile=2 to 6]) of perceived symptom-inducing foods than healthy children (median=2 [25% to 75% quartile=0 to 4]; χ(2)=28.6; P<0.001). Children with IBS avoided more foods (median=2 [25% to 75% quartile=1 to 4]) than healthy children (median=0 [25% to 75% quartile=0 to 2.75]; χ(2)=20.8; P<0.001). The number of self-perceived food intolerances was weakly associated (r value range= -0.17 to 0.21) with pain frequency, pain severity, somatization, anxiety, functional disability, and decreased quality of life. CONCLUSIONS: Children with IBS have a high prevalence of self-perceived food intolerances. The number of these intolerances is weakly associated with measures of IBS severity.

Dynamic regulatory network controlling TH17 cell differentiation.

Despite their importance, the molecular circuits that control the differentiation of naive T cells remain largely unknown. Recent studies that reconstructed regulatory networks in mammalian cells have focused on short-term responses and relied on perturbation-based approaches that cannot be readily applied to primary T cells. Here we combine transcriptional profiling at high temporal resolution, novel computational algorithms, and innovative nanowire-based perturbation tools to systematically derive and experimentally validate a model of the dynamic regulatory network that controls the differentiation of mouse TH17 cells, a proinflammatory T-cell subset that has been implicated in the pathogenesis of multiple autoimmune diseases. The TH17 transcriptional network consists of two self-reinforcing, but mutually antagonistic, modules, with 12 novel regulators, the coupled action of which may be essential for maintaining the balance between TH17 and other CD4(+) T-cell subsets. Our study identifies and validates 39 regulatory factors, embeds them within a comprehensive temporal network and reveals its organizational principles; it also highlights novel drug targets for controlling TH17 cell differentiation.