Browsing by Subject "Conserved Sequence"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    A conserved enhancer regulates Il9 expression in multiple lineages
    (Nature Research, 2018-11-15) Koh, Byunghee; Qayum, Amina Abdul; Srivastava, Rajneesh; Fu, Yongyao; Ulrich, Benjamin J.; Janga, Sarath Chandra; Kaplan, Mark H.; Pediatrics, School of Medicine
    Cytokine genes are regulated by multiple regulatory elements that confer tissue-specific and activation-dependent expression. The cis-regulatory elements of the gene encoding IL-9, a cytokine that promotes allergy, autoimmune inflammation and tumor immunity, have not been defined. Here we identify an enhancer (CNS-25) upstream of the Il9 gene that binds most transcription factors (TFs) that promote Il9 gene expression. Deletion of the enhancer in the mouse germline alters transcription factor binding to the remaining Il9 regulatory elements, and results in diminished IL-9 production in multiple cell types including Th9 cells, and attenuates IL-9-dependent immune responses. Moreover, deletion of the homologous enhancer (CNS-18) in primary human Th9 cultures results in significant decrease of IL-9 production. Thus, Il9 CNS-25/IL9 CNS-18 is a critical and conserved regulatory element for IL-9 production.
  • Thumbnail Image
    Item
    HINCUTs in cancer: hypoxia-induced noncoding ultraconserved transcripts
    (Nature Publishing Group, 2013-12) Ferdin, J.; Nishida, N.; Wu, X.; Nicoloso, M. S.; Shah, M. Y.; Devlin, C.; Ling, H.; Shimizu, M.; Kumar, K.; Cortez, M. A.; Ferracin, M.; Bi, Y.; Yang, D.; Czerniak, B.; Zhang, W.; Schmittgen, T. D.; Voorhoeve, M. P.; Reginato, M. J.; Negrini, M.; Davuluri, R. V.; Kunej, T.; Ivan, M.; Calin, G. A.; Department of Medicine, IU School of Medicine
    Recent data have linked hypoxia, a classic feature of the tumor microenvironment, to the function of specific microRNAs (miRNAs) however, whether hypoxia affects other types of noncoding transcripts is currently unknown. Starting from a genome-wide expression profiling, we demonstrate for the first time a functional link between oxygen deprivation and the modulation of long noncoding transcripts from ultraconserved regions, termed transcribed-ultraconserved regions (T-UCRs). Interestingly, several hypoxia-upregulated T-UCRs, henceforth named ‘hypoxia-induced noncoding ultraconserved transcripts' (HINCUTs), are also overexpressed in clinical samples from colon cancer patients. We show that these T-UCRs are predominantly nuclear and that the hypoxia-inducible factor (HIF) is at least partly responsible for the induction of several members of this group. One specific HINCUT, uc.475 (or HINCUT-1) is part of a retained intron of the host protein-coding gene, O-linked N-acetylglucosamine transferase, which is overexpressed in epithelial cancer types. Consistent with the hypothesis that T-UCRs have important function in tumor formation, HINCUT-1 supports cell proliferation specifically under hypoxic conditions and may be critical for optimal O-GlcNAcylation of proteins when oxygen tension is limiting. Our data gives a first glimpse of a novel functional hypoxic network comprising protein-coding transcripts and noncoding RNAs (ncRNAs) from the T-UCRs category.