Peptidyl argininedeiminase 2 CpG island in multiple sclerosis white matter is hypomethylated.
In previous studies, we documented increased citrullinated myelin basic protein (MBP) was present in MBP isolated from multiple sclerosis (MS) normal appearing white matter (NAWM). This increase was due to the myelin enzyme peptidyl argininedeiminase 2 (PAD2). In this study, we show that methylation of cytosine of the PAD2 promoter in DNA from MS NAWM was decreased to one-third of the level of that in DNA from normal white matter. The PAD2 promoter in DNA from thymus obtained from the same MS patients and white matter DNA from Alzheimer's, Huntington's, and Parkinson's was not hypomethylated. DNA demethylase activity in supernatants prepared from NAWM of MS patients was 2-fold higher than the DNA demethylase from normal, Alzheimer's, Huntington's and Parkinson's disease white matter. The amount of PAD2 enzyme and citrullinated MBP was increased in MS NAWM. The decreased methylation of cytosines in the PAD2 promoter may explain the increased synthesis of PAD2 protein that is responsible for the increased amount of citrullinated MBP, which in turn results in loss of myelin stability in MS brain.
Mastronardi
Fabrizio G
FG
Molecular Structure and Function, The Hospital for Sick Children, Toronto, Ontario, Canada. fabrizio@sickkids.ca
Noor
Abdul
A
Wood
D Denise
DD
Paton
Tara
T
Moscarello
Mario A
MA
D044503:5-Methylcytosine / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000201:enzymology*; D002956:Citrulline / Q000378:metabolism; D018899:CpG Islands / Q000502:physiology*; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D004277:DNA, Single-Stranded / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D006867:Hydrolases / Q000378:metabolism*; D008745:Methylation; D009103:Multiple Sclerosis / Q000201:enzymology*; D004676:Myelin Basic Protein / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D000080064:Protein-Arginine Deiminase Type 2; D000076342:Protein-Arginine Deiminases; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013447:Sulfites / Q000494:pharmacology; D013950:Thymus Gland / Q000378:metabolism
D004277:DNA, Single-Stranded; D004676:Myelin Basic Protein; D013447:Sulfites; D002956:Citrulline; D044503:5-Methylcytosine; D004247:DNA; D006867:Hydrolases; C000620352:PADI2 protein, human; D000080064:Protein-Arginine Deiminase Type 2; D000076342:Protein-Arginine Deiminases