Tissue-specific transcriptional programming of macrophages controls the microRNA transcriptome targeting multiple functional pathways

TL;DR

This paper shows how tissue-specific programming of macrophages, especially through GATA6, controls microRNA expression, which in turn affects immune and cell cycle functions.

Contribution

The study reveals that GATA6 regulates specific microRNAs in macrophages, impacting their functional specialization and response to stimuli.

Findings

GATA6 deficiency in macrophages leads to altered microRNA expression, including miR-146a, miR-223, and miR-203.

miR-708 is significantly dysregulated in GATA6-deficient macrophages, affecting immune and cell cycle pathways.

Overexpression of miR-708 in macrophages alters 167 mRNAs, demonstrating functional downregulation of key targets.

Abstract

Recent interest in the biology and function of peritoneal tissue resident macrophages (pMΦ) has led to a better understanding of their cellular origin, programming, and renewal. The programming of pMΦ is dependent on microenvironmental cues and tissue-specific transcription factors, including GATA6. However, the contribution of microRNAs remains poorly defined. We conducted a detailed analysis of the impact of GATA6 deficiency on microRNA expression in mouse pMΦ. Our data suggest that for many of the pMΦ, microRNA composition may be established during tissue specialization and that the effect of GATA6 knockout is largely unable to be rescued in the adult by exogenous GATA6. The data are consistent with GATA6 modulating the expression pattern of specific microRNAs, directly or indirectly, and including miR-146a, miR-223, and miR-203 established by the lineage-determining transcription factor PU.1, to achieve a differentiated pMΦ phenotype. Lastly, we showed a significant dysregulation of miR-708 in pMΦ in the absence of GATA6 during homeostasis and in response to LPS/IFN-γ stimulation. Overexpression of miR-708 in mouse pMΦ in vivo altered 167 mRNA species demonstrating functional downregulation of predicted targets, including cell immune responses and cell cycle regulation. In conclusion, we demonstrate dependence of the microRNA transcriptome on tissue-specific programming of tissue macrophages as exemplified by the role of GATA6 in pMΦ specialization.

Figures