Epigenomic Evaluation of Cholangiocyte Transforming Growth Factor-β Signaling Identifies a Selective Role for Histone 3 Lysine 9 Acetylation in Biliary Fibrosis.
Epigenomic Evaluation of Cholangiocyte Transforming Growth Factor-β Signaling Identifies a Selective Role for Histone 3 Lysine 9 Acetylation in Biliary Fibrosis.
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胆管细胞转化生长因子-β信号的表观基因组评估确定了组蛋白3赖氨酸9乙酰化在胆汁性纤维化中的选择性作用。
DOI：
10.1053/j.gastro.2020.10.008
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发表时间：
2021-03
期刊：
影响因子：
29.4
通讯作者：
Huebert RC
中科院分区：
文献类型：
--
作者：
Aseem SO;Jalan-Sakrikar N;Chi C;Navarro-Corcuera A;De Assuncao TM;Hamdan FH;Chowdhury S;Banales JM;Johnsen SA;Shah VH;Huebert RC
转化生长因子β(转化生长因子β)上调胆管细胞来源的信号，从而激活肌成纤维细胞，促进纤维化。利用表观基因组学和转录学方法，我们试图区分转化生长因子β下游介导纤维化信号转录的表观遗传激活机制。ChIP-SEQ和RNA-SEQ检测转化生长因子β刺激后的组蛋白修饰和转录变化。组蛋白修饰和乙酰转移酶的占有率通过芯片分析得到确认。转座酶可及染色质测序(ATAC-SEQ)用于研究染色质可及性的变化。取胆管细胞系和原代胆管细胞进行体外研究。以MDR2−/−和3，5-二乙氧基碳环-1，4-二氢氯(DDC)喂养的小鼠为动物模型。转化生长因子β刺激引起组蛋白3赖氨酸27乙酰化(H3K27ac)的广泛改变，并与转化生长因子β介导的整体转录有关。相反，组蛋白3赖氨酸9乙酰化(H3K9ac)在一小部分染色质部位获得，并与纤维化途径有关。这些途径包括肝星状细胞(HSC)激活物如纤维连接蛋白1(FN1)和SERPINE1的过度表达。这些基因的启动子在转化生长因子β后表现出H3K9ac的富集性。在引起H3K9ac的乙酰基转移酶中，胆管细胞主要表达赖氨酸乙酰基转移酶2A(KAT2A)。抑制KAT2a或H3K9ac的siRNA抑制可阻止转化生长因子β介导的Fn1和SerPINE的增加。SMAD3 CHIP-SEQ和ATAC-SEQ表明转化生长因子β介导的H3K9ac是通过SMAD信号发生的，共定位和基因敲除研究证实了这一点。药物抑制或胆管细胞选择性缺失Kat2a对小鼠胆汁纤维化模型具有保护作用。胆管细胞表达的HSC激活信号通过SMAD依赖、KAT2A介导、H3K9ac等途径发生，可靶向预防胆道纤维化。利用表观基因组学和转录学相结合的方法，本研究定义了转化生长因子β下游的表观遗传学机制，该机制介导了胆管细胞中纤维化基因网络的转录。
Transforming growth factor β (TGFβ) upregulates cholangiocyte-derived signals that activate myofibroblasts and promote fibrosis. Using epigenomic and transcriptomic approaches, we sought to distinguish the epigenetic activation mechanisms downstream of TGFβ that mediate transcription of fibrogenic signals. ChIP-seq and RNA-seq were performed to assess histone modifications and transcriptional changes following TGFβ stimulation. Histone modifications and acetyltransferase occupancy were confirmed using ChIP assays. Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) was utilized to investigate changes in chromatin accessibility. Cholangiocyte cell lines and primary cholangiocytes were used for in vitro studies. Mdr2−/− and 3,5-diethoxycarboncyl-1,4-dihydrocollidine (DDC) fed mice were used as animal models. TGFβ stimulation caused widespread changes in histone 3 lysine 27 acetylation (H3K27ac), and was associated with global TGFβ-mediated transcription. In contrast, histone 3 lysine 9 acetylation (H3K9ac) was gained in a smaller group of chromatin sites and was associated with fibrosis pathways. These pathways included overexpression of hepatic stellate cell (HSC) activators such as fibronectin 1 (FN1) and SERPINE1. The promoters of these genes showed H3K9ac enrichment following TGFβ. Of the acetyltransferases responsible for H3K9ac, cholangiocytes predominantly express Lysine Acetyltransferases 2A (KAT2A). siRNA knockdown of KAT2A or H3K9ac inhibition prevented the TGFβ-mediated increase in FN1 and SERPINE. SMAD3 ChIP-seq and ATAC-seq suggested that TGFβ-mediated H3K9ac occurs through SMAD signaling, which was confirmed using co-localization and genetic knockdown studies. Pharmacologic inhibition or cholangiocyte-selective deletion of Kat2a was protective in mouse models of biliary fibrosis. Cholangiocyte expression of HSC-activating signals occurs through SMAD-dependent, KAT2A-mediated, H3K9ac, and can be targeted to prevent biliary fibrosis. Using combined epigenomic and transcriptomic approaches, this study defines an epigenetic mechanism downstream of TGFβ that mediates the transcription of a fibrogenic gene network in cholangiocytes.
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影响因子：
5.2
作者：
Liu, Yujie;Bao, Chunrong;Hancock, Wayne W.
通讯作者：
Hancock, Wayne W.
影响因子：
13.5
作者：
Arbelaiz, Ander;Azkargorta, Mikel;Banales, Jesus M.
通讯作者：
Banales, Jesus M.
DOI：
10.1016/j.bbadis.2017.07.024
发表时间：
2018-04-01
影响因子：
6.2
作者：
Pinto, Claudio;Giordano, Debora Maria;Marzioni, Marco
通讯作者：
Marzioni, Marco
影响因子：
4.8
作者：
O'Hara, Steven P.;Splinter, Patrick L.;LaRusso, Nicholas F.
通讯作者：
LaRusso, Nicholas F.
TGFβ 信号的背景
DOI：
10.1038/nrm3434
发表时间：
2012-10
期刊：
Nature reviews. Molecular cell biology
影响因子：
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作者：
通讯作者：
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