Acetyl-CoA metabolism drives epigenome change and contributes to carcinogenesis risk in fatty liver disease.
Acetyl-CoA metabolism drives epigenome change and contributes to carcinogenesis risk in fatty liver disease.
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DOI：
10.1186/s13073-022-01071-5
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发表时间：
2022-06-23
期刊：
影响因子：
12.3
通讯作者：
中科院分区：
文献类型：
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作者：
非酒精性脂肪性肝病（NAFLD）相关肝细胞癌（HCC）的发病率在全球范围内不断增加，但导致HCC驱动突变的癌前肝细胞的步骤尚不清楚。在这里，我们提供的证据表明，代谢驱动的组蛋白高乙酰化脂肪肝细胞可以增加DNA损伤，启动致癌作用。在来自高脂肪饮食或高果糖饮食啮齿动物模型的肝脏样品以及培养的永生化人肝细胞（IHH细胞）中评估了整体表观遗传状态。通过计算代谢建模以及通过用代谢和表观遗传抑制剂操纵IHH细胞，研究了脂肪变性、组蛋白乙酰化和DNA损伤之间的联系机制。对IHH细胞进行染色质免疫沉淀和下一代测序（ChIP-seq）和转录组（RNA-seq）分析。在IHH细胞模型和来自酒精相关肝病和NAFLD患者的癌前脂肪肝样本的基因组序列数据之间比较突变位置和模式。在高果糖或高脂肪饮食的啮齿动物脂肪变性肝脏中，全基因组蛋白乙酰化增加。在体外，脂肪变性使染色质松弛并增加DNA损伤标记物γ H2 AX，这通过抑制乙酰辅酶A产生而逆转。脂肪变性相关的乙酰化和γ H2 AX在肝细胞和人脂肪肝中端粒近端区域的基因簇中富集，该区域含有HCC肿瘤抑制因子。代谢驱动的表观遗传变化区域也增加了NAFLD和酒精相关肝病患者非癌组织中的DNA突变水平。最后，基因组规模的网络建模表明，氧化还原平衡可能是这一机制的关键贡献者。组蛋白异常乙酰化促进脂肪变性肝细胞的DNA损伤，是肝细胞癌发生的潜在起始事件。在线版本包含补充材料，可通过10.1186/s13073-022-01071-5获得。
The incidence of non-alcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC) is increasing worldwide, but the steps in precancerous hepatocytes which lead to HCC driver mutations are not well understood. Here we provide evidence that metabolically driven histone hyperacetylation in steatotic hepatocytes can increase DNA damage to initiate carcinogenesis. Global epigenetic state was assessed in liver samples from high-fat diet or high-fructose diet rodent models, as well as in cultured immortalized human hepatocytes (IHH cells). The mechanisms linking steatosis, histone acetylation and DNA damage were investigated by computational metabolic modelling as well as through manipulation of IHH cells with metabolic and epigenetic inhibitors. Chromatin immunoprecipitation and next-generation sequencing (ChIP-seq) and transcriptome (RNA-seq) analyses were performed on IHH cells. Mutation locations and patterns were compared between the IHH cell model and genome sequence data from preneoplastic fatty liver samples from patients with alcohol-related liver disease and NAFLD. Genome-wide histone acetylation was increased in steatotic livers of rodents fed high-fructose or high-fat diet. In vitro, steatosis relaxed chromatin and increased DNA damage marker γH2AX, which was reversed by inhibiting acetyl-CoA production. Steatosis-associated acetylation and γH2AX were enriched at gene clusters in telomere-proximal regions which contained HCC tumour suppressors in hepatocytes and human fatty livers. Regions of metabolically driven epigenetic change also had increased levels of DNA mutation in non-cancerous tissue from NAFLD and alcohol-related liver disease patients. Finally, genome-scale network modelling indicated that redox balance could be a key contributor to this mechanism. Abnormal histone hyperacetylation facilitates DNA damage in steatotic hepatocytes and is a potential initiating event in hepatocellular carcinogenesis. The online version contains supplementary material available at 10.1186/s13073-022-01071-5.
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影响因子：
29.4
作者：
Kanwal F;Kramer JR;Mapakshi S;Natarajan Y;Chayanupatkul M;Richardson PA;Li L;Desiderio R;Thrift AP;Asch SM;Chu J;El-Serag HB
通讯作者：
El-Serag HB
影响因子：
--
作者：
Gentilini D;Scala S;Gaudenzi G;Garagnani P;Capri M;Cescon M;Grazi GL;Bacalini MG;Pisoni S;Dicitore A;Circelli L;Santagata S;Izzo F;Di Blasio AM;Persani L;Franceschi C;Vitale G
通讯作者：
Vitale G
DOI：
10.1126/science.aaz8455
发表时间：
2020-04-24
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gilan O;Rioja I;Knezevic K;Bell MJ;Yeung MM;Harker NR;Lam EYN;Chung CW;Bamborough P;Petretich M;Urh M;Atkinson SJ;Bassil AK;Roberts EJ;Vassiliadis D;Burr ML;Preston AGS;Wellaway C;Werner T;Gray JR;Michon AM;Gobbetti T;Kumar V;Soden PE;Haynes A;Vappiani J;Tough DF;Taylor S;Dawson SJ;Bantscheff M;Lindon M;Drewes G;Demont EH;Daniels DL;Grandi P;Prinjha RK;Dawson MA
通讯作者：
Dawson MA
中性粒细胞以ROS依赖性方式诱导旁分泌端粒功能障碍和衰老。
DOI：
10.15252/embj.2020106048
发表时间：
2021-05-03
期刊：
The EMBO journal
影响因子：
--
作者：
Lagnado A;Leslie J;Ruchaud-Sparagano MH;Victorelli S;Hirsova P;Ogrodnik M;Collins AL;Vizioli MG;Habiballa L;Saretzki G;Evans SA;Salmonowicz H;Hruby A;Geh D;Pavelko KD;Dolan D;Reeves HL;Grellscheid S;Wilson CH;Pandanaboyana S;Doolittle M;von Zglinicki T;Oakley F;Gallage S;Wilson CL;Birch J;Carroll B;Chapman J;Heikenwalder M;Neretti N;Khosla S;Masuda CA;Tchkonia T;Kirkland JL;Jurk D;Mann DA;Passos JF
通讯作者：
Passos JF
影响因子：
25.7
作者：
Aravinthan, Aloysious;Scarpini, Cinzia;Alexander, Graeme
通讯作者：
Alexander, Graeme