Project description:Polyglutamine expansion is associated with pathogenic protein aggregation in neurodegenerative disorders. However, long polyglutamine tracts are also found in many transcription factors (TFs), such as FOXP2, a TF implicated in human speech. Here, we explore how FOXP2 and other glutamine-rich TFs avoid unscheduled assembly. Throughout interphase, DNA binding, irrespective of sequence specificity, has a solubilizing effect. During mitosis, multiple phosphorylation events promote FOXP2’s eviction from chromatin and supplant the solubilizing function of DNA. Further, human-specific amino-acid substitutions linked to the evolution of speech map to a mitotic phospho-patch, the ‘EVO patch’, and reduce the propensity of the human FOXP2 to assemble. Fusing the pathogenic form of Huntingtin to either a DNA binding domain, a phospho-mimetic variant of this ‘EVO patch’ or a negatively charged peptide is sufficient to diminish assembly formation, suggesting that hijacking mechanisms governing solubility of glutamine-rich TFs may offer new strategies for treatment of polyQ expansion diseases.
Project description:References:
1. Xiaomei Zhu, Lan Yin, Leroy Hood, David Galas and Ping Ao, Efficiency, Robustness and Stochasticity of Gene Regulatory networks in Systems biology: Lambda switch as a working example, 2006.
2. Adam Arkin, John Ross and Harley H. McAdams, Stochastic kinetic analysis of developmental pathway bifurcation in phage lambda-infected Escherichia coli cells, 1998, Genetics, 149: 1633-1648.
3. GenBank sequence: NC_001416 is the whole genome sequence of phage lambda.
Project description:Evodiamine (Evo), a kind of alkaloid mostly extracted from Tetradium ruticarpum, which has many pharmacological functions, such as antidiarrheal, antiemetic, and antiulcer effects. In this study, the effects of Evo were investigated in DSS-induced ulcerative colitis (UC) mice and C57BL/6-ApcMinC/Gpt mice with colorectal cancer (CRC). The results showed Evo not only sup-pressed the weight loss and the shorthen of colon, decreased disease activity index (DAI) and ameliorated the pathological alteration of colon in UC mice, but also inhibited the numbers and sizes of colonic tumor of ApcMinC/Gpt mice. Meanwhiles, Evo regulated nuclear factor-kappa B (NF-κB) related signal pathways to mediate various cytokines such as interleukins (Ils), tumor necrosis factor-α (TNF-α) to achieve anti-inflammatory and anti-tumor effects. In SW480 and Caco cells, Evo reduced the cell viabilities, promoted the mitochondrial membrane potential (MMP) and caused the over-accumulation of intracellular reactive oxygen species (ROS). Theoretical evi-dences indicated Evo binding NF-κB may be useful to contain ordered domain (α helix) in NF-κB, which can induce NF-κB to perform its function. Our results provide experimental and theoretical evidence that Evo might be promising and effective treatments in clinics for UC and CRC.
Project description:Lambda interferons IFNL1-3 mediate antiviral immunity by inducing interferon sensitive genes (ISGs) in epithelial tissues. Contrarily, a variant creating the functional gene IFNL4 is associated with impaired clearance of hepatitis C virus (HCV) despite of higher liver expression of ISGs in untreated HCV patients. We aimed to explore IFNL4 signaling mechanism by comparing expression profiles from human hepatic cell line clones with genetic modifications influencing the ISG signaling pathway (IFNLR1/IL10R2 knockouts, IFNL4/IFNL3 expression stimulation by transfection).
Project description:The Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has had devastating impacts on our global society. Although vaccines and monoclonal antibody countermeasures have reduced the morbidity and mortality associated with SARS-CoV-2 infection, variants with constellations of mutations in the spike gene threaten their efficacy. Therefore, antiviral interventions that are resistant to further virus evolution may be needed. Here, we show IFN-λ protects against SARS-CoV-2 B.1.351 (Beta) and B.1.1529 (Omicron) variants in three strains of conventional and human ACE2 transgenic mice. Prophylaxis or therapy with nasally-delivered IFN-λ2 limited infection of historical or variant (B.1.351 and B.1.1.529) SARS-CoV-2 strains in both the upper and lower respiratory tracts without causing excessive inflammation. In the lung, IFN-λ was produced preferentially in epithelial cells and acted on radio-resistant cells to protect against of SARS-CoV-2 infection. Thus, inhaled IFN-λ may have promise as a treatment for evolving SARS-CoV-2 variants that develop resistance to antibody-based countermeasures.
Project description:The healthy intestine mounts immune responses to microbiota to maintain homeostasis, which includes basal production of interferon cytokines. Previous work showed that Type III Interferon (IFN-λ) stimulates localized pockets of interferon-stimulated genes (ISGs) in the adult mouse intestinal epithelium at homeostasis that provide preemptive protection from viral pathogens. Here, we demonstrate that a major source of homeostatic IFN-λ production in the intestine is a population of epithelium-associated plasmacytoid dendritic cells (pDC). These pDC are recruited to the intestine by bacterial microbiota colonization, and pDC depletion or bone marrow reconstitution with IFN-λ-deficient pDC results in reduced homeostatic ISGs in the intestinal epithelium. Notably, intestinal pDC preferentially produce IFN-λ over Type I IFNs whereas splenic pDC produce more Type I IFNs. Comparison of splenic and intestinal pDC reveal tissue-specific changes in gene expression and genomic accessibility, including evidence of response to transforming growth factor beta (TGF-β) in the intestine. Isolated gut pDC produce more IFN-λ that splenic pDC upon stimulation, and pre-treatment of a human pDC cell line with TGF-β results in enhanced production of IFN-λ upon stimulation. This study implicates pDC as important sources of homeostatic IFN-λ in the intestine and defines the role of barrier cytokine TGF-β in regulating IFN types produced by pDC upon stimulation. Reprogramming of recruited pDC by tissue cytokines may have important implications for balancing effective antimicrobial responses with damaging inflammation at barrier tissues.