YB-1 DNA-BINDING PROTEIN REPRESSES INTERFERON-GAMMA ACTIVATION OF CLASS-II MAJOR HISTOCOMPATIBILITY COMPLEX GENES
JOURNAL OF EXPERIMENTAL MEDICINE
Authors: TING, JPY; PAINTER, A; ZELEZNIKLE, NJ; MACDONALD, G; MOORE, TM; BROWN, A; SCHWARTZ, BD
Abstract
Interferon gamma (IFN-gamma) is the most potent inducer of class II major histocompatibility complex (MHC) genes. This induction is uniquely mediated by three DNA elements in the promoter region of class II MHC genes. One of these DNA elements, Y, contains an inverted CCAAT box. Previously, we have screened a lambda t11 library for Y-binding proteins and identified the YB-1 gene. Here we provide evidence that YB-1 can repress the IFN-gamma induction of class II MHC promoter as well as the Invariant chain (Ii) gene which also contains a Y element in its promoter This was demonstrated by cotransfecting a YB-1 expression vector with promoter-reporter gene constructs. As an alternate approach, an efficient transient transfection system was developed which resulted in a >70% transfection efficiency. Transfection of YB-1 by this procedure resulted in the near abrogation of IFN-gamma induced HLA-DR antigen and mRNA expression. These findings show the functional suppression of class II MHC gene induction by the YB-1 protein.
Deep Resequencing of Ulcerative Colitis-Associated Genes Identifies Novel Variants in Candidate Genes in the Korean Population
INFLAMMATORY BOWEL DISEASES
Authors: Moon, Chang Mo; Kim, Seung Won; Ahn, Jae Bum; Ma, Hyun Woo; Che, Xiumei; Kim, Tae Il; Kim, Won Ho; Cheon, Jae Hee
Abstract
Background: Genome-wide association studies and meta-analyses have revealed the genetic background of ulcerative colitis (UC) by identifying common variants. However, these variants do not fully explain the disease variance in UC. To identify novel variants, we performed deep resequencing of UC-associated genes in Korean UC patients and subsequently investigated the functional roles of identified susceptibility genes. Methods: We performed targeted deep resequencing of 108 genes in 24 Korean UC patients and then performed association analysis with data from 126 healthy controls. We validated these variants using 2-stage replication studies including 793 UC patients and 783 controls. We performed in silico and pathway analyses and functional analyses. Results: The combined analysis including 2 replication studies identified 6 novel susceptibility loci and reconfirmed 10 previously reported loci. Among the novel single nucleotide variants (SNVs), rs10035653 in C5orf55 (P = 2.08 x 10(-3); OR = 1.50), rs41417449 in BTNL2 (P = 1.27 x 10(-2); OR = 1.32), rs3117099 in HCG23 (P = 9.98 x 10(-6); OR = 1.40), rs7192 in HLA-DRA (P = 6.95 x 10(-9); OR = 1.57), and rs3744246 in ORMDL3 (P = 2.21 x 10(-2); OR = 1.21) were identified as causal variants, whereas rs713669 in IL17REL (P = 2.69 x 10(-2); OR = 0.84) as a protective variant for UC. When correcting multiple testing, 3 novel SNVs (rs41417449 in BTNL2, rs3744246 in ORMDL3, and rs713669 in IL17REL) and 4 previously reported SNVs did not reach a statistical significance. Functional study suggested that SNVs of BTNL2 and C5orf55 exacerbated the inflammatory response both in vitro and in vivo. Conclusions: This study identified 3 novel susceptibility loci and validated 6 previously reported SNVs for UC through deep resequencing in Koreans and revealed the functional roles of BTNL2 and C5orf55.