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Methylation and microRNA-mediated epigenetic regulation of SOCS3

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Abstract

Epigenetic gene silencing of several genes causes different pathological conditions in humans, and DNA methylation has been identified as one of the key mechanisms that underlie this evolutionarily conserved phenomenon associated with developmental and pathological gene regulation. Recent advances in the miRNA technology with high throughput analysis of gene regulation further increased our understanding on the role of miRNAs regulating multiple gene expression. There is increasing evidence supporting that the miRNAs not only regulate gene expression but they also are involved in the hypermethylation of promoter sequences, which cumulatively contributes to the epigenetic gene silencing. Here, we critically evaluated the recent progress on the transcriptional regulation of an important suppressor protein that inhibits cytokine-mediated signaling, SOCS3, whose expression is directly regulated both by promoter methylation and also by microRNAs, affecting its vital cell regulating functions. SOCS3 was identified as a potent inhibitor of Jak/Stat signaling pathway which is frequently upregulated in several pathologies, including cardiovascular disease, cancer, diabetes, viral infections, and the expression of SOCS3 was inhibited or greatly reduced due to hypermethylation of the CpG islands in its promoter region or suppression of its expression by different microRNAs. Additionally, we discuss key intracellular signaling pathways regulated by SOCS3 involving cellular events, including cell proliferation, cell growth, cell migration and apoptosis. Identification of the pathway intermediates as specific targets would not only aid in the development of novel therapeutic drugs, but, would also assist in developing new treatment strategies that could successfully be employed in combination therapy to target multiple signaling pathways.

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Acknowledgments

Research reported in this publication was supported by the National Institutes of Health research grants R01HL090580, R01HL104516, and R01HL112597 to DKA. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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  1. Center for Clinical and Translational Science, Creighton University School of Medicine, Omaha, NE, 68178, USA

    Chandra S. Boosani

  2. Center for Clinical and Translational Science, Creighton University School of Medicine, Criss II, Room 510, 2500 California Plaza, Omaha, NE, 68178, USA

    Devendra K. Agrawal

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Boosani, C.S., Agrawal, D.K. Methylation and microRNA-mediated epigenetic regulation of SOCS3. Mol Biol Rep 42, 853–872 (2015). https://doi.org/10.1007/s11033-015-3860-3

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