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

Publication date: Available online 2 March 2019Source: Biochimica et Biophysica Acta (BBA) - Gene Regulatory MechanismsAuthor(s): Can Shi, Jessica Miley, Alison Nottingham, Toshifumi Morooka, Domenick A. Prosdocimo, Daniel I. SimonAbstractLeukocyte 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 β2-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-I...

Source: Biochimica et Biophysica Acta (BBA) Gene Regulatory Mechanisms - March 4, 2019 Category: Genetics & Stem Cells Source Type: research