Hepatic deficiency of the pioneer transcription factor FoxA restricts hepatitis B virus biosynthesis by the developmental regulation of viral DNA methylation.
Hepatic deficiency of the pioneer transcription factor FoxA restricts hepatitis B virus biosynthesis by the developmental regulation of viral DNA methylation.
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DOI：
10.1371/journal.ppat.1006239
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发表时间：
2017-02
期刊：
影响因子：
6.7
通讯作者：
McLachlan A
中科院分区：
文献类型：
--
作者：
McFadden VC;Shalaby RE;Iram S;Oropeza CE;Landolfi JA;Lyubimov AV;Maienschein-Cline M;Green SJ;Kaestner KH;McLachlan A
FoxA家族的先驱转录因子调节B型肝炎病毒（HBV）的转录，并因此调节病毒复制。慢性感染HBV转基因小鼠模型中肝细胞特异性FoxA缺陷阻止了病毒DNA基因组的转录，这是出生后肝成熟过程中发育控制的5-甲基胞嘧啶残基转化为胞嘧啶失败的结果。这些观察结果表明，先锋转录因子，如FoxA，标志着在细胞分化程序中的后续发育步骤中表达的基因，通过逆转其靶基因的DNA甲基化状态来介导它们的作用，以允许它们在发育过程中出现适当的组织特异性转录因子组合时随后表达。此外，由于FoxA缺陷型HBV转基因小鼠是可行的，特定的发育时间、丰度和先锋因子表达的同种型必须允许所有必需的肝脏基因表达以足以支持足够的肝功能的水平发生。这意味着先驱转录因子可以识别和标记其靶基因在不同的发展方式依赖于，至少部分地，在增强子和启动子调控序列元件内的结合位点的FoxA的浓度和亲和力。与HBV相比，FoxA先锋因子对细胞基因表达的这种选择性标记可能为HBV基因表达的特异性沉默提供机会，从而解决慢性HBV感染，慢性HBV感染每年导致全球约100万人死于肝硬化和肝细胞癌。本研究证实了在肝脏成熟过程中FoxA表达与体内DNA甲基化引起的基因沉默之间的联系。FoxA表达不足导致DNA甲基化导致选择性发育调控的B型肝炎病毒（HBV）沉默。据我们所知，这是第一次在体内证明，先锋因子如FoxA通过介导其靶基因的发育去甲基化，导致其组织特异性基因表达来发挥作用。此外，我们的研究结果强烈暗示，标记的细胞靶基因的后续转录后，在发展是依赖于水平和时间的FoxA表达加上其亲和力的增强子和启动子区域内的靶序列。因此，这些研究结果表明，在发育过程中适当控制FoxA活性可能会导致核HBV共价闭合环状DNA的甲基化转录失活，从而解决慢性HBV感染。这代表了当前疗法无法达到的临床目标，因此表明了治愈这种慢性感染的潜在途径，这种慢性感染每年导致约100万人死亡。
The FoxA family of pioneer transcription factors regulates hepatitis B virus (HBV) transcription, and hence viral replication. Hepatocyte-specific FoxA-deficiency in the HBV transgenic mouse model of chronic infection prevents the transcription of the viral DNA genome as a result of the failure of the developmentally controlled conversion of 5-methylcytosine residues to cytosine during postnatal hepatic maturation. These observations suggest that pioneer transcription factors such as FoxA, which mark genes for expression at subsequent developmental steps in the cellular differentiation program, mediate their effects by reversing the DNA methylation status of their target genes to permit their ensuing expression when the appropriate tissue-specific transcription factor combinations arise during development. Furthermore, as the FoxA-deficient HBV transgenic mice are viable, the specific developmental timing, abundance and isoform type of pioneer factor expression must permit all essential liver gene expression to occur at a level sufficient to support adequate liver function. This implies that pioneer transcription factors can recognize and mark their target genes in distinct developmental manners dependent upon, at least in part, the concentration and affinity of FoxA for its binding sites within enhancer and promoter regulatory sequence elements. This selective marking of cellular genes for expression by the FoxA pioneer factor compared to HBV may offer the opportunity for the specific silencing of HBV gene expression and hence the resolution of chronic HBV infections which are responsible for approximately one million deaths worldwide annually due to liver cirrhosis and hepatocellular carcinoma. This study demonstrates the connection between FoxA expression and gene silencing by DNA methylation in vivo during liver maturation. Insufficient FoxA expression results in selective developmentally regulated hepatitis B virus (HBV) silencing by DNA methylation. To our knowledge, this is the first in vivo demonstration that pioneer factors such as FoxA function by mediating the developmental demethylation of their target genes, leading to their tissue specific gene expression. Furthermore, our results strongly imply that the marking of cellular target genes for subsequent transcription later in development is dependent upon the level and timing of FoxA expression plus its affinity for its target sequences within enhancer and promoter regions. Consequently, these findings suggest that the appropriate control of FoxA activity during development could lead to the transcriptional inactivation of nuclear HBV covalently closed circular DNA by methylation and hence resolution of chronic HBV infection. This represents a clinical goal that current therapies are unable to attain, and hence suggests a potential route to a cure for this chronic infection which kills approximately 1 million individuals annually.