Natural antisense transcript for hyaluronan synthase 2 (HAS2-AS1) induces transcription of HAS2 via protein O-GlcNAcylation

Autor: Eugenia Karousou, Dona C. Love, Maria Grandoch, Timothy Bowen, Giancarlo De Luca, Alexander Oberhuber, Raffaella Cinquetti, Sara Deleonibus, Davide Vigetti, Vincent C. Hascall, Paola Moretto, Manuela Viola, Alberto Passi, Jens W. Fischer, Maria Luisa D'Angelo, John A. Hanover
Rok vydání: 2014
Předmět:
Male
endocrine system
Cytoplasm
Transcription
Genetic
Molecular Sequence Data
Myocytes
Smooth Muscle
Glycobiology and Extracellular Matrices
macromolecular substances
Biology
Hyaluronan Synthase 2
N-Acetylglucosaminyltransferases
Biochemistry
Gene Expression Regulation
Enzymologic
Acetylglucosamine
Epigenesis
Genetic
Mice
Transcription (biology)
hemic and lymphatic diseases
medicine
Animals
Humans
Gene Silencing
RNA
Messenger
Glucuronosyltransferase
Promoter Regions
Genetic
neoplasms
Molecular Biology
Transcription factor
Aorta
Regulation of gene expression
Cell Nucleus
Mice
Knockout
Messenger RNA
Base Sequence
Models
Genetic
Monosaccharides
Cell Biology
Molecular biology
Chromatin
Antisense RNA
carbohydrates (lipids)
Cell nucleus
medicine.anatomical_structure
lipids (amino acids
peptides
and proteins)
Hyaluronan Synthases
Zdroj: The Journal of biological chemistry. 289(42)
ISSN: 1083-351X
Popis: Changes in the microenvironment organization within vascular walls are critical events in the pathogenesis of vascular pathologies, including atherosclerosis and restenosis. Hyaluronan (HA) accumulation into artery walls supports vessel thickening and is involved in many cardiocirculatory diseases. Excessive cytosolic glucose can enter the hexosamine biosynthetic pathway, increase UDP-N-acetylglucosamine (UDP-GlcNAc) availability, and lead to modification of cytosolic proteins via O-linked attachment of the monosaccharide β-N-GlcNAc (O-GlcNAcylation) from UDP-GlcNAc by the enzyme O-GlcNAc transferase. As many cytoplasmic and nuclear proteins can be glycosylated by O-GlcNAc, we studied whether the expression of the HA synthases that synthesize HA could be controlled by O-GlcNAcylation in human aortic smooth muscle cells. Among the three HAS isoenzymes, only HAS2 mRNA increased after O-GlcNAcylation induced by glucosamine treatments or by inhibiting O-GlcNAc transferase with PUGNAC (O-(2-acetamido-2-deoxy-d-glucopyranosylidene)amino-N-phenylcarbamate). We found that the natural antisense transcript of HAS2 (HAS2-AS1) was absolutely necessary to induce the transcription of the HAS2 gene. Moreover, we found that O-GlcNAcylation modulated HAS2-AS1 promoter activation by recruiting the NF-κB subunit p65, but not the HAS2 promoter, whereas HAS2-AS1 natural antisense transcript, working in cis, regulated HAS2 transcription by altering the chromatin structure around the HAS2 proximal promoter via O-GlcNAcylation and acetylation. These results indicate that HAS2 transcription can be finely regulated not only by recruiting transcription factors to the promoter as previously described but also by modulating chromatin accessibility by epigenetic modifications.
Databáze: OpenAIRE
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