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Site‐specific identification and validation of hepatic histone nitration in vivo: Implications for alcohol‐induced liver injury
Author(s) -
Kriss Crystina L.,
Duro Nalvi,
Nadeau Owen W.,
Guergues Jennifer,
ChavezChiang Omar,
CulverCochran Ashley E.,
Chaput Dale,
Varma Sameer,
Stevens Stanley M.
Publication year - 2021
Publication title -
journal of mass spectrometry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 121
eISSN - 1096-9888
pISSN - 1076-5174
DOI - 10.1002/jms.4713
Subject(s) - chemistry , histone , nitrotyrosine , oxidative stress , nitration , liver injury , acetylation , biochemistry , dna , gene , pharmacology , biology , enzyme , nitric oxide synthase , organic chemistry
Oxidative and nitrative stress have been implicated in the molecular mechanisms underlying a variety of biological processes and disease states including cancer, aging, cardiovascular disease, neurological disorders, diabetes, and alcohol‐induced liver injury. One marker of nitrative stress is the formation of 3‐nitrotyrosine, or protein tyrosine nitration (PTN), which has been observed during inflammation and tissue injury; however, the role of PTN in the progression or possibly the pathogenesis of disease is still unclear. We show in a model of alcohol‐induced liver injury that an increase in PTN occurs in hepatocyte nuclei within the liver of wild‐type male C57BL/6J mice following chronic ethanol exposure (28 days). High‐resolution mass spectrometric analysis of isolated hepatic nuclei revealed several novel sites of tyrosine nitration on histone proteins. Histone nitration sites were validated by tandem mass spectrometry (MS/MS) analysis of representative synthetic nitropeptides equivalent in sequence to the respective nitrotyrosine sites identified in vivo. We further investigated the potential structural impact of the novel histone H3 Tyr41 (H3Y41) nitration site identified using molecular dynamics (MD) simulations. MD simulations of the nitrated and non‐nitrated forms of histone H3Y41 showed significant structural changes at the DNA interface upon H3Y41 nitration. The results from this study suggest that, in addition to other known post‐translational modifications that occur on histone proteins (e.g., acetylation and methylation), PTN could induce chromatin structural changes, possibly affecting gene transcription processes associated with the development of alcohol‐induced liver injury.