[HTML][HTML] PU. 1-dependent transcriptional regulation of miR-142 contributes to its hematopoietic cell–specific expression and modulation of IL-6

Y Sun, J Sun, T Tomomi, E Nieves… - The Journal of …, 2013 - journals.aai.org
Y Sun, J Sun, T Tomomi, E Nieves, N Mathewson, H Tamaki, R Evers, P Reddy
The Journal of Immunology, 2013journals.aai.org
MicroRNAs (miRs) have emerged as critical modulators of immune responses, but little is
known about their transcriptional regulation and tissue specificity. miR-142 is specifically
expressed in hematopoietic tissues and plays an important role in regulating immunity. In
this study we identified the key transcriptional elements for regulation of miR-142 and its
impact on TLR4-mediated expression of IL-6. The PU. 1, C/EBPβ, and Runx1 transcription
factor binding sites are conserved and constitutively occupied by the respective transcription …
Abstract
MicroRNAs (miRs) have emerged as critical modulators of immune responses, but little is known about their transcriptional regulation and tissue specificity. miR-142 is specifically expressed in hematopoietic tissues and plays an important role in regulating immunity. In this study we identified the key transcriptional elements for regulation of miR-142 and its impact on TLR4-mediated expression of IL-6. The PU. 1, C/EBPβ, and Runx1 transcription factor binding sites are conserved and constitutively occupied by the respective transcription factors in the miR-142 gene promoter only in the hematopoietic cells. Specific knockdown experiments in hematopoietic cells and rescue experiments in nonhematopoietic cells show that PU. 1 is critical for miR-142 gene expression and that it synergizes with Runx1, C/EBPβ, and CBFβ. Furthermore, TLR4 stimulation enhanced miR-155 whereas experiments with knockdown and mimic expression of miR-155 demonstrated that miR-155 negatively regulates miR-142-3p expression by targeting PU. 1. Thus, TLR4 stimulation represses PU. 1, resulting in downregulation of miR-142 and increased expression of IL-6. These results collectively reveal the direct cis-acting sequences of miR-142 specific promoter and that transcription factor PU. 1 is necessary for its exclusive expression in hematopoietic cells and regulation of IL-6.
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