Resetting the epigenetic histone code in the MRL-lpr/lpr mouse model of lupus by histone deacetylase inhibition.
The baseline level of gene expression varies between healthy controls and systemic lupus erythematosus (SLE) patients, and among SLE patients themselves. These variations may explain the different clinical manifestations and severity of disease observed in SLE. Epigenetic mechanisms, which involve DNA and histone modifications, are predictably associated with distinct transcriptional states. To understand the interplay between various histone modifications, including acetylation and methylation, and lupus disease, we performed differential expression histone modification analysis in splenocytes from the MRL-lpr/lpr mouse model of lupus. Using stable isotope labeling in combination with mass spectrometry, we found global site-specific hypermethylation (except H3 K4 methylation) and hypoacetylation in histone H3 and H4 MRL-lpr/lpr mice compared to control MRL/MPJ mice. Moreover, we have identified novel histone modifications such as H3 K18 methylation, H4 K31 methylation, and H4 K31 acetylation that are differentially expressed in MRL-lpr/lpr mice compared to controls. Finally, in vivo administration of the histone deacetylase inhibitor trichostatin A (TSA) corrected the site-specific hypoacetylation states on H3 and H4 in MRL-lpr/lpr mice with improvement of disease phenotype. Thus, this study is the first to establish the association between aberrant histone codes and pathogenesis of autoimmune disease SLE. These aberrant post-translational histone modifications can therefore be reset with histone deacetylase inhibition in vivo.
Garcia
Benjamin A
BA
Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904, USA.
Busby
Scott A
SA
Shabanowitz
Jeffrey
J
Hunt
Donald F
DF
Mishra
Nilamadhab
N
D000595:Amino Acid Sequence; D000818:Animals; D001327:Autoimmune Diseases / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000737:chemistry; D019175:DNA Methylation; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D005260:Female; D005786:Gene Expression Regulation; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007554:Isotopes; D008180:Lupus Erythematosus, Systemic / Q000378:metabolism; D008177:Lupus Vulgaris / Q000235:genetics* / Q000378:metabolism*; D013058:Mass Spectrometry; D051379:Mice; D019463:Mice, Inbred MRL lpr; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D010641:Phenotype; D011499:Protein Processing, Post-Translational; D017386:Sequence Homology, Amino Acid; D013154:Spleen / Q000166:cytology
D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007554:Isotopes; D010455:Peptides; C012589:trichostatin A; D004247:DNA; D006655:Histone Deacetylases