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MicroRNAs distinguish translational from transcriptional silencing during endotoxin tolerance.
J Biol Chem. 2010 Jul 02; 285(27):20940-51.JB

Abstract

We reported that gene-selective formation of facultative heterochromatin silences transcription of acute inflammatory genes during endotoxin (LPS) tolerance, according to function. We discovered that reversal of the epigenetically silenced transcription restored mRNA levels but not protein synthesis. Here, we find that translation repression of tumor necrosis factor-alpha (TNFalpha) occurs independent of transcription silencing during LPS tolerance. The process required to disrupt protein synthesis followed Toll-like receptor 4 (TLR4)-dependent induction of microRNA (miR)-221, miR-579, and miR-125b, which coupled with RNA-binding proteins TTP, AUF1, and TIAR at the 3'-untranslated region to arrest protein synthesis. TTP and AUF1 proteins linked to miR-221, whereas TIAR coupled with miR-579 and miR-125b. Functional inhibition of miR-221 prevented TNFalpha mRNA degradation, and blocking miR-579 and miR-125b precluded translation arrest. The functional specificity of the TNFalpha 3'-untranslated region was demonstrated using luciferase reporter with mutations in the three putative miRNA binding sites. Post-transcriptional silencing was gene-specific, because it did not affect production of the IkappaBalpha anti-inflammatory protein. These results suggest that TLR4-dependent reprogramming of inflammatory genes is regulated at two separate and distinct levels. The first level of control is mediated by epigenetic modifications at the promoters that control transcription. The second and previously unrecognized level of control is mediated by TLR4-dependent differential expression of miRNAs that exert post-transcriptional controls. The concept of distinct regulation of transcription and translation was confirmed in murine sepsis. We conclude that transcription- and translation-repressive events combine to tightly regulate pro-inflammatory genes during LPS tolerance, a common feature of severe systemic inflammation.

Authors+Show Affiliations

Department of Internal Medicine, Section of Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. melgazza@wfubmc.eduNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

20435889

Citation

El Gazzar, Mohamed, and Charles E. McCall. "MicroRNAs Distinguish Translational From Transcriptional Silencing During Endotoxin Tolerance." The Journal of Biological Chemistry, vol. 285, no. 27, 2010, pp. 20940-51.
El Gazzar M, McCall CE. MicroRNAs distinguish translational from transcriptional silencing during endotoxin tolerance. J Biol Chem. 2010;285(27):20940-51.
El Gazzar, M., & McCall, C. E. (2010). MicroRNAs distinguish translational from transcriptional silencing during endotoxin tolerance. The Journal of Biological Chemistry, 285(27), 20940-51. https://doi.org/10.1074/jbc.M110.115063
El Gazzar M, McCall CE. MicroRNAs Distinguish Translational From Transcriptional Silencing During Endotoxin Tolerance. J Biol Chem. 2010 Jul 2;285(27):20940-51. PubMed PMID: 20435889.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - MicroRNAs distinguish translational from transcriptional silencing during endotoxin tolerance. AU - El Gazzar,Mohamed, AU - McCall,Charles E, Y1 - 2010/04/30/ PY - 2010/5/4/entrez PY - 2010/5/4/pubmed PY - 2010/8/11/medline SP - 20940 EP - 51 JF - The Journal of biological chemistry JO - J Biol Chem VL - 285 IS - 27 N2 - We reported that gene-selective formation of facultative heterochromatin silences transcription of acute inflammatory genes during endotoxin (LPS) tolerance, according to function. We discovered that reversal of the epigenetically silenced transcription restored mRNA levels but not protein synthesis. Here, we find that translation repression of tumor necrosis factor-alpha (TNFalpha) occurs independent of transcription silencing during LPS tolerance. The process required to disrupt protein synthesis followed Toll-like receptor 4 (TLR4)-dependent induction of microRNA (miR)-221, miR-579, and miR-125b, which coupled with RNA-binding proteins TTP, AUF1, and TIAR at the 3'-untranslated region to arrest protein synthesis. TTP and AUF1 proteins linked to miR-221, whereas TIAR coupled with miR-579 and miR-125b. Functional inhibition of miR-221 prevented TNFalpha mRNA degradation, and blocking miR-579 and miR-125b precluded translation arrest. The functional specificity of the TNFalpha 3'-untranslated region was demonstrated using luciferase reporter with mutations in the three putative miRNA binding sites. Post-transcriptional silencing was gene-specific, because it did not affect production of the IkappaBalpha anti-inflammatory protein. These results suggest that TLR4-dependent reprogramming of inflammatory genes is regulated at two separate and distinct levels. The first level of control is mediated by epigenetic modifications at the promoters that control transcription. The second and previously unrecognized level of control is mediated by TLR4-dependent differential expression of miRNAs that exert post-transcriptional controls. The concept of distinct regulation of transcription and translation was confirmed in murine sepsis. We conclude that transcription- and translation-repressive events combine to tightly regulate pro-inflammatory genes during LPS tolerance, a common feature of severe systemic inflammation. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/20435889/MicroRNAs_distinguish_translational_from_transcriptional_silencing_during_endotoxin_tolerance_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(20)57381-X DB - PRIME DP - Unbound Medicine ER -