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MicroRNA-29 regulates T-box transcription factors and interferon-? production in helper T cells.

ABSTRACT: MicroRNA (miRNA)-deficient helper T cells exhibit abnormal IFN-? production and decreased proliferation. However, the contributions of individual miRNAs to this phenotype remain poorly understood. We conducted a screen for miRNA function in primary T cells and identified individual miRNAs that rescue the defects associated with miRNA deficiency. Multiple members of the miR-17 and miR-92 families enhanced miRNA-deficient T cell proliferation whereas miR-29 largely corrected their aberrant interferon-? (IFN-?) expression. Repression of IFN-? production by miR-29 involved direct targeting of both T-bet and Eomes, two transcription factors known to induce IFN-? production. Although not usually expressed at functionally relevant amounts in helper T cells, Eomes was abundant in miRNA-deficient cells and was upregulated after miR-29 inhibition in wild-type cells. These results demonstrate that miR-29 regulates helper T cell differentiation by repressing multiple target genes, including at least two that are independently capable of inducing the T helper 1 (Th1) cell gene expression program.

SUBMITTER: Steiner DF

PROVIDER: S-EPMC3361370 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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MicroRNA-29 regulates T-box transcription factors and interferon-γ production in helper T cells.

Steiner David F DF Thomas Molly F MF Hu Joyce K JK Yang Zhiyong Z Babiarz Joshua E JE Allen Christopher D C CD Matloubian Mehrdad M Blelloch Robert R Ansel K Mark KM

Immunity 20110804 2

MicroRNA (miRNA)-deficient helper T cells exhibit abnormal IFN-γ production and decreased proliferation. However, the contributions of individual miRNAs to this phenotype remain poorly understood. We conducted a screen for miRNA function in primary T cells and identified individual miRNAs that rescue the defects associated with miRNA deficiency. Multiple members of the miR-17 and miR-92 families enhanced miRNA-deficient T cell proliferation whereas miR-29 largely corrected their aberrant interfe ...[more]

PMID: 21820330

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Project description:UNLABELLED: BACKGROUND: The type-II-cytokine IFN-? is a pivotal player in innate immune responses but also assumes functions in controlling tumor cell growth by orchestrating cellular responses against neoplastic cells. The role of IFN-? in melanoma is not fully understood: it is a well-known growth inhibitor of melanoma cells in vitro. On the other hand, IFN-? may also facilitate melanoma progression. While interferon-regulated genes encoding proteins have been intensively studied since decades, the contribution of miRNAs to effects mediated by interferons is an emerging area of research.We recently described a distinct and dynamic regulation of a whole panel of microRNAs (miRNAs) after IFN-?-stimulation. The aim of this study was to analyze the transcriptional regulation of miR-29 family members in detail, identify potential interesting target genes and thus further elucidate a potential signaling pathway IFN-? ? Jak? P-STAT1 ? miR-29 ? miR-29 target genes and its implication for melanoma growth. RESULTS: Here we show that IFN-? induces STAT1-dependently a profound up-regulation of the miR-29 primary cluster pri-29a~b-1 in melanoma cell lines. Furthermore, expression levels of pri-29a~b-1 and mature miR-29a and miR-29b were elevated while the pri-29b-2~c cluster was almost undetectable. We observed an inverse correlation between miR-29a/b expression and the proliferation rate of various melanoma cell lines. This finding could be corroborated in cells transfected with either miR-29 mimics or inhibitors. The IFN-?-induced G1-arrest of melanoma cells involves down-regulation of CDK6, which we proved to be a direct target of miR-29 in these cells. Compared to nevi and normal skin, and metastatic melanoma samples, miR-29a and miR-29b levels were found strikingly elevated in certain patient samples derived from primary melanoma. CONCLUSIONS: Our findings reveal that the miR-29a/b1 cluster is to be included in the group of IFN- and STAT-regulated genes. The up-regulated miR-29 family members may act as effectors of cytokine signalling in melanoma and other cancer cells as well as in the immune system.

Dataset Information

MicroRNA-29 regulates T-box transcription factors and interferon-? production in helper T cells.

Publications

MicroRNA-29 regulates T-box transcription factors and interferon-γ production in helper T cells.

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