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.

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.