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

Czubala, Magdalena A. ORCID: https://orcid.org/0000-0001-9881-1095, Jenkins, Robert H. ORCID: https://orcid.org/0000-0001-8500-9044, Gurney, Mark ORCID: https://orcid.org/0000-0003-1119-6638, Wallace, Leah, Cossins, Benjamin, Dennis, James, Rosas, Marcela ORCID: https://orcid.org/0000-0002-9442-9638, Andrews, Robert, Fraser, Donald ORCID: https://orcid.org/0000-0003-0102-9342 and Taylor, Philip 2024. Tissue-specific transcriptional programming of macrophages controls the microRNA transcriptome targeting multiple functional pathways. Journal of Biological Chemistry , 107244. 10.1016/j.jbc.2024.107244

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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, -223, and -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.

Item Type: Article
Date Type: Published Online
Status: In Press
Schools: Medicine
Publisher: Elsevier
ISSN: 0021-9258
Date of First Compliant Deposit: 2 April 2024
Date of Acceptance: 25 March 2024
Last Modified: 25 May 2024 05:44
URI: https://orca.cardiff.ac.uk/id/eprint/167620

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