Wilson Disease: Intersecting DNA Methylation and Histone Acetylation Regulation of Gene Expression in a Mouse Model of Hepatic Copper Accumulation.
Wilson Disease: Intersecting DNA Methylation and Histone Acetylation Regulation of Gene Expression in a Mouse Model of Hepatic Copper Accumulation.
复制标题
DOI：
10.1016/j.jcmgh.2021.05.020
复制
发表时间：
2021
影响因子：
7.2
通讯作者：
Medici V
中科院分区：
文献类型：
--
作者：
Sarode GV;Neier K;Shibata NM;Shen Y;Goncharov DA;Goncharova EA;Mazi TA;Joshi N;Settles ML;LaSalle JM;Medici V
肝豆状核变性（WD）的发病机制涉及肝和脑铜蓄积，这是由影响ATP 7 B基因的致病性变体以及下游表观遗传和代谢机制引起的。先前在人WD肝脏和血液中以及在杰克逊实验室（Bar Harbor，ME）C3 He-Atp 7 btx-j/J（tx-j）WD小鼠模型中的甲基化组研究揭示了WD的表观遗传特征，包括组蛋白脱乙酰酶（HDAC）5的变化。我们测试的假设，组蛋白乙酰化改变铜超载和异常的DNA甲基化在WD。我们研究了IIa类HDAC 4和HDAC 5和H3 K9/H3 K27组蛋白乙酰化在tx-j小鼠肝脏中与C3 HeB/FeJ（C3 H）对照相比，对3种处理的响应：60%千卡脂肪饮食，D-青霉胺（铜螯合剂）和胆碱（甲基供体）。用载铜肝癌G2细胞进行实验以验证体内研究。在9周的tx-j小鼠中，与普通食物相比，HDAC 5水平在60%千卡脂肪饮食8天后显著增加。在24周的tx-j小鼠中，与C3 H相比，HDAC 4/5水平降低了5至10倍，可能是通过涉及HDAC磷酸化的机制。HDAC 4/5水平受疾病进展的影响，并伴随乙酰化的增加。D-青霉胺和胆碱部分恢复HDAC 4/5和H3 K9 ac/H3 K27 ac至C3 H水平。整合的RNA和染色质免疫沉淀测序分析揭示了调节能量代谢和细胞应激/发育的基因，与C3 H小鼠相比，这些基因反过来又受到组蛋白乙酰化的调节，其中Pparα和Pparγ是最相关的靶点。这些结果表明，IIa类HDAC 4/5的饮食调节，以及随后的H3 K9/H3 K27乙酰化/脱乙酰化可以调节WD发病机制中关键代谢途径的基因表达。
The pathogenesis of Wilson disease (WD) involves hepatic and brain copper accumulation resulting from pathogenic variants affecting the ATP7B gene and downstream epigenetic and metabolic mechanisms. Prior methylome investigations in human WD liver and blood and in the Jackson Laboratory (Bar Harbor, ME) C3He-Atp7btx-j/J (tx-j) WD mouse model revealed an epigenetic signature of WD, including changes in histone deacetylase (HDAC) 5. We tested the hypothesis that histone acetylation is altered with respect to copper overload and aberrant DNA methylation in WD. We investigated class IIa HDAC4 and HDAC5 and H3K9/H3K27 histone acetylation in tx-j mouse livers compared with C3HeB/FeJ (C3H) control in response to 3 treatments: 60% kcal fat diet, D-penicillamine (copper chelator), and choline (methyl group donor). Experiments with copper-loaded hepatoma G2 cells were conducted to validate in vivo studies. In 9-week tx-j mice, HDAC5 levels increased significantly after 8 days of a 60% kcal fat diet compared with chow. In 24-week tx-j mice, HDAC4/5 levels were reduced 5- to 10-fold compared with C3H, likely through mechanisms involving HDAC phosphorylation. HDAC4/5 levels were affected by disease progression and accompanied by increased acetylation. D-penicillamine and choline partially restored HDAC4/5 and H3K9ac/H3K27ac to C3H levels. Integrated RNA and chromatin immunoprecipitation sequencing analyses revealed genes regulating energy metabolism and cellular stress/development, which, in turn, were regulated by histone acetylation in tx-j mice compared with C3H mice, with Pparα and Pparγ among the most relevant targets. These results suggest dietary modulation of class IIa HDAC4/5, and subsequent H3K9/H3K27 acetylation/deacetylation can regulate gene expression in key metabolic pathways in the pathogenesis of WD.
登录
查看更多内容
影响因子：
7.1
作者：
Desai, Vishal;Kaler, Stephen G.
通讯作者：
Kaler, Stephen G.
DOI：
10.1016/j.jcmgh.2018.12.005
发表时间：
2019-01-01
影响因子：
7.2
作者：
Einer, Claudia;Leitzinger, Christin;Zischka, Hans
通讯作者：
Zischka, Hans
影响因子：
5.2
作者：
Chen, Jianxu;Chen, Jiandi;Li, Jian
通讯作者：
Li, Jian
影响因子：
3.3
作者：
Lei L;Xiaoyi S;Fuchang L
通讯作者：
Fuchang L
影响因子：
4.8
作者：
Li, XF;Song, S;Kao, HY
通讯作者：
Kao, HY