Bardag-Gorce Fawzia, Dedes Jennifer, French Barbara A, Oliva Joan V, Li Jun, French Samuel W
Department of Pathology, Harbor-UCLA Medical Center, 1000 W. Carson St., Torrance, CA 90509, USA.
Exp Mol Pathol. 2007 Oct;83(2):160-8. doi: 10.1016/j.yexmp.2007.03.003. Epub 2007 Mar 30.
Microarrays were done on the livers of mice fed DDC for 10 weeks, withdrawn 1 month (DDC primed livers) and refed 6 days, and compared with mice fed the control diet. The expression of a large number of genes changed when DDC was fed or refed. A Venn diagram analysis identified 649 genes where gene expression was changed in the same direction. The epigenetic memory of the DDC primed liver involved an increase in the expression of ubiquitin D, alpha fetoprotein, connective tissue growth factor, integrin beta 2, DNA methyl transferase 3a and DNA damage-inducible 45 gamma. DNA methyl transferase 3b was down-regulated as was Cbp/p300. When DDC was refed, DNA methyltransferase and histone deacetylase were up-regulated as shown by microarray analysis. Histone3 lysine9 acetylation was increased by DDC and DDC refeeding and DNA methyltransferases were not changed as shown by Western blot analysis. The data suggest the concept that the epigenetic memory that explains why DDC primed hepatocytes form MBs in 7 days of DDC refeeding is primarily the result of epigenetic modifications of gene expression through changes in histone acetylation and methylation, as well as DNA methylation.
对喂食DDC 10周、停药1个月（DDC预处理肝脏）并再次喂食6天的小鼠肝脏进行微阵列分析，并与喂食对照饮食的小鼠进行比较。喂食或再次喂食DDC时，大量基因的表达发生了变化。维恩图分析确定了649个基因，其基因表达在相同方向上发生了变化。DDC预处理肝脏的表观遗传记忆涉及泛素D、甲胎蛋白、结缔组织生长因子、整合素β2、DNA甲基转移酶3a和DNA损伤诱导因子45γ的表达增加。DNA甲基转移酶3b以及Cbp/p300被下调。微阵列分析显示，再次喂食DDC时，DNA甲基转移酶和组蛋白脱乙酰酶上调。蛋白质免疫印迹分析表明，DDC和再次喂食DDC可增加组蛋白3赖氨酸9乙酰化，而DNA甲基转移酶未发生变化。这些数据表明了这样一个概念，即解释DDC预处理的肝细胞在再次喂食DDC 7天内形成MBs的表观遗传记忆主要是基因表达通过组蛋白乙酰化和甲基化以及DNA甲基化变化进行表观遗传修饰的结果。
