Methylation and microRNA-mediated epigenetic regulation of SOCS3

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.

Figure 1

Figure 1a: Identification of the CpG island in the 10.4 kb human SOCS3 genomic sequence using CpG plot (EMBOSS). Figure shows the presence of a distinct CpG island which encompasses the promoter and coding sequence of human SOCS3 gene. Figure 1b: Characterization of CpG island within the genomic sequence of human SOCS3. Figure shows the close proximity of individual CpG methylation sites within the CpG island that is highlighted in blue. Figure 1c: MicroRNAs that can bind to human DNMT1 transcript. The binding sites of different miRNAs was analyzed at www.microrna.org, which shows the results of DNMT1 and its related sequences from NCBI (NM_001379, NM_001130823, AB209413, AK122759, BC092517). Figure 1d: MicroRNAs that can bind to human SOCS3 transcript. The binding sites of different miRNAs was analyzed at www.microrna.org,which shows the results of SOCS3 sequence from NCBI (NM_003955.4).

Figure 1

Figure 1a: Identification of the CpG island in the 10.4 kb human SOCS3 genomic sequence using CpG plot (EMBOSS). Figure shows the presence of a distinct CpG island which encompasses the promoter and coding sequence of human SOCS3 gene. Figure 1b: Characterization of CpG island within the genomic sequence of human SOCS3. Figure shows the close proximity of individual CpG methylation sites within the CpG island that is highlighted in blue. Figure 1c: MicroRNAs that can bind to human DNMT1 transcript. The binding sites of different miRNAs was analyzed at www.microrna.org, which shows the results of DNMT1 and its related sequences from NCBI (NM_001379, NM_001130823, AB209413, AK122759, BC092517). Figure 1d: MicroRNAs that can bind to human SOCS3 transcript. The binding sites of different miRNAs was analyzed at www.microrna.org,which shows the results of SOCS3 sequence from NCBI (NM_003955.4).

Figure 2

Possible SOCS3 interventions in various human diseases. Figure illustrates the effector pathways that are mediated by SOCS3 in different human diseases.

Figure 3

Intracellular signaling mechanisms regulated by SOCS3