Leukocyte integrin signaling regulates FOXP1 gene expression via FOXP1-IT1 long non-coding RNA-mediated IRAK1 pathway.

Autor: Shi C; Harrington Heart & Vascular Institute, University Hospitals Cleveland Medical Center, Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. Electronic address: can.shi@case.edu., Miley J; Harrington Heart & Vascular Institute, University Hospitals Cleveland Medical Center, Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA., Nottingham A; Harrington Heart & Vascular Institute, University Hospitals Cleveland Medical Center, Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA., Morooka T; Harrington Heart & Vascular Institute, University Hospitals Cleveland Medical Center, Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA., Prosdocimo DA; Harrington Heart & Vascular Institute, University Hospitals Cleveland Medical Center, Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA., Simon DI; Harrington Heart & Vascular Institute, University Hospitals Cleveland Medical Center, Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Jazyk: angličtina
Zdroj: Biochimica et biophysica acta. Gene regulatory mechanisms [Biochim Biophys Acta Gene Regul Mech] 2019 Apr; Vol. 1862 (4), pp. 493-508. Date of Electronic Publication: 2019 Mar 02.
DOI: 10.1016/j.bbagrm.2019.02.008
Abstrakt: Leukocyte integrin-dependent downregulation of the transcription factor FOXP1 is required for monocyte differentiation and macrophage functions, but the precise gene regulatory mechanism is unknown. Here, we identify multi-promoter structure (P1, P2, and P3) of the human FOXP1 gene. Clustering of the β 2 -leukocyte integrin Mac-1 downregulated transcription from these promoters. We extend our prior observation that IL-1 receptor-associated kinase 1 (IRAK1) is physically associated with Mac-1 and provide evidence that IRAK1 is a potent suppressor of human FOXP1 promoter. IRAK1 reduced phosphorylation of histone deacetylase 4 (HDAC4) via inhibiting phosphorylation of calcium/calmodulin dependent protein kinase II delta (CaMKIIδ), thereby promoting recruitment of HDAC4 to P1 chromatin. A novel human FOXP1 intronic transcript 1 (FOXP1-IT1) long non-coding RNA (lncRNA), whose gene is embedded within that of FOXP1, has been cloned and found to bind directly to HDAC4 and regulate FOXP1 in cis manner. Overexpression of FOXP1-IT1 counteracted Mac-1 clustering-dependent downregulation of FOXP1, reduced IRAK1 downregulation of HDAC4 phosphorylation, and attenuated differentiation of THP-1 monocytic cells. In contrast, Mac-1 clustering inhibited FOXP1-IT1 expression with reduced binding to HDAC4 as well as phosphorylation of CaMKIIδ to activate the IRAK1 signaling pathway. Importantly, both IRAK1 and HDAC4 inhibitors significantly reduced integrin clustering-triggered downregulation of FOXP1 expression in purified human blood monocytes. Identification of this Mac-1/IRAK-1/FOXP1-IT1/HDAC4 signaling network featuring crosstalk between lncRNA and epigenetic factor for the regulation of FOXP1 expression provides new targets for anti-inflammatory therapeutics.
(Copyright © 2019 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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