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 Crystina  Kriss

Crystina Kriss

Crystina Kriss



Advisor : Brant Burkhardt



Hello and thanks for visiting! I am Crystina and am currently a Ph.D. candidate in the Stevens Laboratory. My project focuses on the identification and characterization of novel ethanol-induced histone modifications in the liver. Epigenetic dysregulation through alcohol-induced changes in DNA methylation and histone modifications has been implicated in several alcohol-related disorders such as alcoholic liver disease (ALD). Our lab has been actively studying the impact of alcohol (ethanol)-induced oxidative stress and metabolic alterations and how these factors affect changes in hepatic histone modifications. Specifically, ethanol-induced changes in hepatic histone modifications can occur through either direct oxidative modification of histones or through ethanol-induced changes in cofactor availability of various histone-modifying enzymes. In relation to the oxidative modification of histones, we have discovered that tyrosine nitration, a post-translational modification resulting from increased production of both reactive nitrogen and oxygen species, can occur selectively on histone proteins in the liver after chronic ethanol exposure in mice. Using mass spectrometry-based proteomics, several sites of histone tyrosine nitration were identified and validated. One site in particular on histone H3, H3Y41, was selected for further validation using a custom antibody generated for that site. Moreover, molecular dynamics simulations were performed to determine the potential structural impact of H3Y41 nitration and initial results suggest H3Y41 nitration induces a distinct opening of the H3-DNA interface, but without affecting the overall histone structure. In terms of an indirect mechanism, ethanol metabolism in the liver can influence lysine acetylation of proteins through NAD+-dependent sirtuin activity. Sirtuin activity is altered due to increases in NADH during ethanol metabolism. Alcohol metabolism also results in the formation of acetate that can be used to produce acetyl-CoA that can be used by histone acetyltransferases to acetylate lysine residues. We use metabolic tracing experiments in primary hepatocytes, both in vitro and in vivo, in order to site-specifically quantify the contribution of histone acetylation from acetyl-CoA that results from the metabolism of ethanol. Future studies aim to determine the functional consequences of these novel histone modifications and their role in acute and chronic ethanol-induced liver injury.