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PMID:22269951

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Citation

Bandyopadhyay, S, Harris, DP, Adams, GN, Lause, GE, McHugh, A, Tillmaand, EG, Money, A, Willard, B, Fox, PL and Dicorleto, PE (2012) HOXA9 methylation by PRMT5 is essential for endothelial cell expression of leukocyte adhesion molecules. Mol. Cell. Biol. 32:1202-13

Abstract

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.

Links

PubMed PMC3302442 Online version:10.1128/MCB.05977-11

Keywords

E-Selectin/genetics; E-Selectin/immunology; Gene Expression Regulation; Homeodomain Proteins/genetics; Homeodomain Proteins/immunology; Homeodomain Proteins/metabolism; Human Umbilical Vein Endothelial Cells/immunology; Human Umbilical Vein Endothelial Cells/metabolism; Humans; Methylation; Nuclear Proteins/genetics; Nuclear Proteins/immunology; Nuclear Proteins/metabolism; Promoter Regions, Genetic; Tumor Necrosis Factor-alpha/immunology; Vascular Cell Adhesion Molecule-1/genetics; Vascular Cell Adhesion Molecule-1/immunology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:ANM5

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P31269

F

Seeded From UniProt

complete

HUMAN:ANM5

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P31269

F

Seeded From UniProt

complete

HUMAN:HXA9

enables

GO:0019899: enzyme binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O14744

F

Seeded From UniProt

complete

HUMAN:HXA9

involved_in

GO:0042118: endothelial cell activation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HXA9

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O14744

F

Seeded From UniProt

complete

HUMAN:ANM5

involved_in

GO:0042118: endothelial cell activation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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