Methyl Deficiency, Alterations in Global Histone Modifications, and Carcinogenesis

Abstract

The methyl-deficient model of endogenous hepatocarcinogenesis in rodents is unique in that dietary omission rather than the addition of chemical carcinogens leads to tumor formation. Thus, the biochemical and molecular events predisposing to cancer in this model result from chronic metabolic stress and provide an ideal model system to study progressive alterations that occur during carcinogenesis. Moreover, epigenetic alterations imposed by this diet are believed to be 1 of the main mechanisms responsible for malignant transformation of rat liver cells. In this study we examined the changes in global histone modification patterns in liver during hepatocarcinogenesis induced by methyl deficiency. Feeding animals the methyl-deficient diet (MDD) led to progressive loss of histone H4 lysine 20 trimethylation (H4K20me3), H3 lysine 9 trimethylation (H3K9me3), and histone H3 lysine 9 (H3K9ac) and histone H4 lysine 16 (H4K16ac) acetylation. A considerable decrease of H4K20me3 and H3K9ac was also detected in liver tumors induced by MDD. In contrast, liver tumors displayed an increase in H3K9me3 and H4K16ac. To determine the possible mechanism of alterations of histone modifications, we analyzed the expression of histone-modifying enzymes in liver during hepatocarcinogenesis. The expression of Suv4-20h2 and RIZ1 histone methyltransferases (HMTs) steadily decreased along with the development of liver tumors and reached its lowest level in tumor tissue, whereas the expression of Suv39-h1 HMT and histone acetyltransferase 1 (HAT1) substantially increased in tumors. These results illustrate the complexity and importance of histone modification changes in the etiology of hepatocarcinogenesis induced by MDD.

NAD+-dependent deacetylation of H4 lysine 16 by class III HDACs

“…This was accompanied by a global increase in both H4K16Ac and H3K9me3 and with a decrease in H4K20me3 and H3K9Ac (Pogribny et al, 2007). Although these findings argue in favor of H4K16 hypoacetylation being a phenomenon of cellular transformation, a caveat to these studies is that this specific model of MDDpromoted tumorigenesis in rat livers is due to metabolic deficiency and it might be mechanistically very peculiar compared to the rest of cancers.…”

A new perspective on neural tube defects: Folic acid and microRNA misexpression

“…Folate deficiency occurs in about 10% of the US population and low folic acid has been associated with chromosomal damage, including strand breaks and misincorporation of uracil into DNA (Blount et al, 1997;Duthie and Hawdon, 1998;Pogribny et al, 2006b). Folic acid deficiency was linked to the formation of NTDs by the observation that pregnant women who took medication that interfered or antagonized folate metabolism (aminopterin, carbamazpine, and valproic acid) had a greater number of children with spina bifida (Johnson et al, 1999).…”

“…There are currently 24 known sites of methylation: 17 on lysine residues and seven on arginine residues (Pogribny et al, 2006b). Pogribny et al fed rats a methyl deficient diet (MDD) and found a significant decrease in trimethylation of histone3-lysine9 (H3K9) and histone4-lysine20 (H4K20); H3K9 trimethylation is necessary for cells to differentiate and its loss favors proliferation.…”

“…Methylated DNA also attracts methyl-binding proteins that recruit histone deacetylase protein complexes (Pogribny et al, 2006b;Santos et al, 2002) and loss of DNA methylation has been shown to increase histone acetylation. Histone hypoacetylation prevents differentiation of ESCs in vitro, and histone methylation can influence DNA methylation indicating that the methylation status of DNA and histones are intricately linked, and perturbances in proper methylation of either may alter normal repression or expression of genes during development (Jackson et al, 2004).…”

“…Research is conflicting in regards to polymorphisms of the MTHFR gene and their contribution to NTDs (Choi et al, 2005;Mathers, 2005;Pogribny et al, 2006b;Sahara et al, 2007, Shang et al, 2008Stegmann et al, FIG. 2. Dnmt1 pathway and consequences if miR-221 and miR-222 are overexpressed or if miR-17 is underexpressed.…”