HOXA9 Methylation by PRMT5 Is Essential for Endothelial Cell Expression of Leukocyte Adhesion Molecules
| Autor: | Emily G. Tillmaand, Daniel P. Harris, Paul E. DiCorleto, Paul L. Fox, Belinda Willard, Angela Money, Anne McHugh, Gregory E. Lause, Gregory N. Adams, Smarajit Bandyopadhyay |
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| Rok vydání: | 2012 |
| Předmět: |
Homeodomain Proteins
Small interfering RNA Tumor Necrosis Factor-alpha Cell adhesion molecule Leukocyte adhesion molecule Protein arginine methyltransferase 5 Nuclear Proteins Vascular Cell Adhesion Molecule-1 Articles Cell Biology Methylation Biology Molecular biology Gene Expression Regulation Coactivator Human Umbilical Vein Endothelial Cells Humans E-Selectin Promoter Regions Genetic Molecular Biology Transcription factor Chromatin immunoprecipitation |
| Zdroj: | Molecular and Cellular Biology. 32:1202-1213 |
| ISSN: | 1098-5549 |
| DOI: | 10.1128/mcb.05977-11 |
| Popis: | The induction of proinflammatory proteins in stimulated endothelial cells (EC) requires activation of multiple transcription programs. The homeobox transcription factor HOXA9 has an important regulatory role in cytokine induction of the EC-leukocyte adhesion molecules (ELAM) E-selectin and vascular cell adhesion molecule 1 (VCAM-1). However, the mechanism underlying stimulus-dependent activation of HOXA9 is completely unknown. Here, we elucidate the molecular mechanism of HOXA9 activation by tumor necrosis factor alpha (TNF-α) and show an unexpected requirement for arginine methylation by protein arginine methyltransferase 5 (PRMT5). PRMT5 was identified as a TNF-α-dependent binding partner of HOXA9 by mass spectrometry. Small interfering RNA (siRNA)-mediated depletion of PRMT5 abrogated stimulus-dependent HOXA9 methylation with concomitant loss in E-selectin or VCAM-1 induction. Chromatin immunoprecipitation analysis revealed that PRMT5 is recruited to the E-selectin promoter following transient HOXA9 binding to its cognate recognition sequence. PRMT5 induces symmetric dimethylation of Arg140 on HOXA9, an event essential for E-selectin induction. In summary, PRMT5 is a critical coactivator component in a newly defined, HOXA9-containing transcription complex. Moreover, stimulus-dependent methylation of HOXA9 is essential for ELAM expression during the EC inflammatory response. |
| Databáze: | OpenAIRE |
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