title: Reprogramming of the MHC-I and its regulation by NFκB in human-induced pluripotent stem cells.
abstract: The immunogenicity of human pluripotent stem cells plays a major role in their potential use in the clinic. We show that, during their reprogramming, human-induced pluripotent stem (iPS) cells downregulate expression of human leukocyte antigen (HLA)-A/B/C and β2 microglobulin (β2M), the two components of major histocompatibility complex-I (MHC-I). MHC-I expression in iPS cells can be restored by differentiation or treatment with interferon-gamma (IFNγ). To analyze the molecular mechanisms that regulate the expression of the MHC-I molecules in human iPS cells, we searched for correlation between the expression of HLA-A/B/C and β2M and the expression of transcription factors that bind to the promoter of these genes. Our results show a significant positive correlation between MHC-I expression and expression of the nuclear factors, nuclear factor kappa B 1 (NFκB1) and RelA, at the levels of RNA, protein and was confirmed by chromatin binding. Concordantly, we detected robust levels of NFκB1 and RelA proteins in the nucleus of somatic cells but not in the iPS cell derived from them. Overexpression of NFκB1 and RelA in undifferentiated pluripotent stem cells led to induction in expression of MHC-I, whereas silencing NFκB1 and RelA by small hairpin RNA decreased the expression of β2M after IFNγ treatment. Our data point to the critical role of NFκB proteins in regulating the MHC-I expression in human pluripotent stem cells.
authors.affiliation: Stem Cell Unit, Department of Genetics, Institute of Life Sciences, The Hebrew University, Jerusalem, Israel.
authors.forename: Marjorie
authors.initials: M
authors.lastname: Pick
authors.forename: Daniel
authors.initials: D
authors.lastname: Ronen
authors.forename: Ofra
authors.initials: O
authors.lastname: Yanuka
authors.forename: Nissim
authors.initials: N
authors.lastname: Benvenisty
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D015536:Down-Regulation; D005347:Fibroblasts / Q000166:cytology; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007120:Immunochemistry; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000276:immunology* / Q000502:physiology*; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology; D046228:Microarray Analysis; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D051996:Transcription Factor RelA / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001613:beta 2-Microglobulin / Q000096:biosynthesis / Q000276:immunology
chemical_list: D015395:Histocompatibility Antigens Class I; D016328:NF-kappa B; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C498143:RELA protein, human; D051996:Transcription Factor RelA; D001613:beta 2-Microglobulin; D007371:Interferon-gamma