Coordinated regulation of miR-155 and miR-146a genes during induction of endotoxin tolerance in macrophages

Christina Doxaki; Sotirios C. Kampranis; Aristides G. Eliopoulos; Charalampos Spilianakis; Christos Tsatsanis

doi:10.4049/jimmunol.1500615

Coordinated regulation of miR-155 and miR-146a genes during induction of endotoxin tolerance in macrophages

Christina Doxaki, Sotirios C. Kampranis, Aristides G. Eliopoulos, Charalampos Spilianakis, Christos Tsatsanis

48 Citations (Scopus)

Abstract

Endotoxin tolerance occurs to protect the organism from hyperactivation of innate immune responses, primarily mediated by macrophages. Regulation of endotoxin tolerance occurs at multiple levels of cell responses and requires significant changes in gene expression. In the process of macrophage activation, induced expression of microRNA (miR)-155 and miR-146a contributes to the regulation of the inflammatory response and endotoxin tolerance. In this article, we demonstrate that expression of both miRNAs is coordinately regulated during endotoxin tolerance by a complex mechanism that involves monoallelic interchromosomal association, alterations in histone methyl marks, and transcription factor binding. Upon activation of naive macrophages, Histone3 was trimethylated at lysine4 and NFkBp65 was bound on both miR-155 and miR-146a gene loci. However, at the stage of endotoxin tolerance, both miR gene loci were occupied by C/EBPb, NFkBp50, and the repressive Histone3 marks trimethylation of K9 of H3. DNA fluorescence in situ hybridization experiments revealed monoallelic interchromosomal colocalization of miR-155 and miR-146a gene loci at the stage of endotoxin tolerance, whereas RNA-DNA-fluorescence in situ hybridization experiments showed that the colocalized alleles were silenced, suggesting a common repression mechanism. Genetic ablation of Akt1, which is known to abrogate endotoxin tolerance, abolished induction of loci colocalization and C/EBPb binding, further supporting that this mechanism occurs specifically in endotoxin tolerance. Overall, this study demonstrates that two miRNAs are coordinately regulated via gene colocalization at the three-dimensional chromatin space, same transcriptional machinery, and similar Histone3 methylation profile, contributing to the development of endotoxin tolerance.

Original language	English
Journal	The Journal of Immunology
Volume	195
Issue number	12
Pages (from-to)	5750-5761
Number of pages	12
ISSN	0022-1767
DOIs	https://doi.org/10.4049/jimmunol.1500615
Publication status	Published - 15 Dec 2015
Externally published	Yes

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@article{5f9b4e06edd147f590459884371edde2,

title = "Coordinated regulation of miR-155 and miR-146a genes during induction of endotoxin tolerance in macrophages",

abstract = "Endotoxin tolerance occurs to protect the organism from hyperactivation of innate immune responses, primarily mediated by macrophages. Regulation of endotoxin tolerance occurs at multiple levels of cell responses and requires significant changes in gene expression. In the process of macrophage activation, induced expression of microRNA (miR)-155 and miR-146a contributes to the regulation of the inflammatory response and endotoxin tolerance. In this article, we demonstrate that expression of both miRNAs is coordinately regulated during endotoxin tolerance by a complex mechanism that involves monoallelic interchromosomal association, alterations in histone methyl marks, and transcription factor binding. Upon activation of naive macrophages, Histone3 was trimethylated at lysine4 and NFkBp65 was bound on both miR-155 and miR-146a gene loci. However, at the stage of endotoxin tolerance, both miR gene loci were occupied by C/EBPb, NFkBp50, and the repressive Histone3 marks trimethylation of K9 of H3. DNA fluorescence in situ hybridization experiments revealed monoallelic interchromosomal colocalization of miR-155 and miR-146a gene loci at the stage of endotoxin tolerance, whereas RNA-DNA-fluorescence in situ hybridization experiments showed that the colocalized alleles were silenced, suggesting a common repression mechanism. Genetic ablation of Akt1, which is known to abrogate endotoxin tolerance, abolished induction of loci colocalization and C/EBPb binding, further supporting that this mechanism occurs specifically in endotoxin tolerance. Overall, this study demonstrates that two miRNAs are coordinately regulated via gene colocalization at the three-dimensional chromatin space, same transcriptional machinery, and similar Histone3 methylation profile, contributing to the development of endotoxin tolerance.",

author = "Christina Doxaki and Kampranis, {Sotirios C.} and Eliopoulos, {Aristides G.} and Charalampos Spilianakis and Christos Tsatsanis",

note = "Copyright {\textcopyright} 2015 by The American Association of Immunologists, Inc.",

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T1 - Coordinated regulation of miR-155 and miR-146a genes during induction of endotoxin tolerance in macrophages

AU - Doxaki, Christina

AU - Kampranis, Sotirios C.

AU - Eliopoulos, Aristides G.

AU - Spilianakis, Charalampos

AU - Tsatsanis, Christos

PY - 2015/12/15

Y1 - 2015/12/15

N2 - Endotoxin tolerance occurs to protect the organism from hyperactivation of innate immune responses, primarily mediated by macrophages. Regulation of endotoxin tolerance occurs at multiple levels of cell responses and requires significant changes in gene expression. In the process of macrophage activation, induced expression of microRNA (miR)-155 and miR-146a contributes to the regulation of the inflammatory response and endotoxin tolerance. In this article, we demonstrate that expression of both miRNAs is coordinately regulated during endotoxin tolerance by a complex mechanism that involves monoallelic interchromosomal association, alterations in histone methyl marks, and transcription factor binding. Upon activation of naive macrophages, Histone3 was trimethylated at lysine4 and NFkBp65 was bound on both miR-155 and miR-146a gene loci. However, at the stage of endotoxin tolerance, both miR gene loci were occupied by C/EBPb, NFkBp50, and the repressive Histone3 marks trimethylation of K9 of H3. DNA fluorescence in situ hybridization experiments revealed monoallelic interchromosomal colocalization of miR-155 and miR-146a gene loci at the stage of endotoxin tolerance, whereas RNA-DNA-fluorescence in situ hybridization experiments showed that the colocalized alleles were silenced, suggesting a common repression mechanism. Genetic ablation of Akt1, which is known to abrogate endotoxin tolerance, abolished induction of loci colocalization and C/EBPb binding, further supporting that this mechanism occurs specifically in endotoxin tolerance. Overall, this study demonstrates that two miRNAs are coordinately regulated via gene colocalization at the three-dimensional chromatin space, same transcriptional machinery, and similar Histone3 methylation profile, contributing to the development of endotoxin tolerance.

AB - Endotoxin tolerance occurs to protect the organism from hyperactivation of innate immune responses, primarily mediated by macrophages. Regulation of endotoxin tolerance occurs at multiple levels of cell responses and requires significant changes in gene expression. In the process of macrophage activation, induced expression of microRNA (miR)-155 and miR-146a contributes to the regulation of the inflammatory response and endotoxin tolerance. In this article, we demonstrate that expression of both miRNAs is coordinately regulated during endotoxin tolerance by a complex mechanism that involves monoallelic interchromosomal association, alterations in histone methyl marks, and transcription factor binding. Upon activation of naive macrophages, Histone3 was trimethylated at lysine4 and NFkBp65 was bound on both miR-155 and miR-146a gene loci. However, at the stage of endotoxin tolerance, both miR gene loci were occupied by C/EBPb, NFkBp50, and the repressive Histone3 marks trimethylation of K9 of H3. DNA fluorescence in situ hybridization experiments revealed monoallelic interchromosomal colocalization of miR-155 and miR-146a gene loci at the stage of endotoxin tolerance, whereas RNA-DNA-fluorescence in situ hybridization experiments showed that the colocalized alleles were silenced, suggesting a common repression mechanism. Genetic ablation of Akt1, which is known to abrogate endotoxin tolerance, abolished induction of loci colocalization and C/EBPb binding, further supporting that this mechanism occurs specifically in endotoxin tolerance. Overall, this study demonstrates that two miRNAs are coordinately regulated via gene colocalization at the three-dimensional chromatin space, same transcriptional machinery, and similar Histone3 methylation profile, contributing to the development of endotoxin tolerance.

U2 - 10.4049/jimmunol.1500615

DO - 10.4049/jimmunol.1500615

M3 - Journal article

C2 - 26538391

SN - 0022-1767

VL - 195

SP - 5750

EP - 5761

JO - Journal of Immunology

JF - Journal of Immunology

IS - 12

ER -

Coordinated regulation of miR-155 and miR-146a genes during induction of endotoxin tolerance in macrophages

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