Epigenetics Insights最新文献

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Dynamics of DNA Methylation Reprogramming Influenced by X Chromosome Dosage in Induced Pluripotent Stem Cells. X染色体剂量对诱导多能干细胞DNA甲基化重编程的影响。

IF 2.2 Q3 Biochemistry, Genetics and Molecular Biology

Epigenetics Insights

Pub Date : 2018-10-14 eCollection Date: 2018-01-01 DOI: 10.1177/2516865718802931

Adrian Janiszewski, Juan Song, Lotte Vanheer, Natalie De Geest, Vincent Pasque

How the epigenome of one cell type is remodeled during reprogramming into another unrelated type of cell remains unclear. Overexpression of transcription factors in somatic cells enables the induction of induced pluripotent stem cells (iPSCs). This process entails genome-wide remodeling of DNA methylation, chromatin, and transcription. Recent work suggests that the number of active X chromosomes present in a cell influences remodeling of DNA methylation during somatic cell reprogramming to mouse iPSCs. Female iPSCs with 2 active X chromosomes display global DNA hypomethylation, whereas male XY iPSCs show DNA methylation levels similar to the somatic cells they are derived from. Global DNA methylation erasure in female iPSCs takes place genome-wide and involves repression of DNA methyltransferases. However, on loss of one X chromosome, female iPSCs acquire a DNA methylation landscape resembling that of XY iPSCs. Therefore, it is the X chromosome dosage that dictates global DNA methylation levels in iPSCs. Here, we discuss the evidence that links X chromosome dosage with the regulation of DNA methylation in pluripotent stem cells. We focus on iPSCs reprogramming studies, where X chromosome status is a novel factor impacting our understanding of epigenetic remodeling.

一种细胞类型的表观基因组是如何在重编程成另一种不相关的细胞类型的过程中被重塑的，目前还不清楚。体细胞中转录因子的过度表达能够诱导多能干细胞(iPSCs)。这一过程需要DNA甲基化、染色质和转录的全基因组重塑。最近的研究表明，细胞中存在的活性X染色体的数量会影响体细胞重编程到小鼠iPSCs过程中DNA甲基化的重塑。具有2条活性X染色体的女性iPSCs显示整体DNA低甲基化，而男性XY iPSCs显示与其来源的体细胞相似的DNA甲基化水平。在女性iPSCs中，DNA甲基化消除发生在全基因组范围内，涉及DNA甲基转移酶的抑制。然而，当丢失一条X染色体时，雌性iPSCs获得与XY iPSCs相似的DNA甲基化景观。因此，是X染色体剂量决定了iPSCs中DNA甲基化水平。在这里，我们讨论了X染色体剂量与多能干细胞DNA甲基化调控的证据。我们专注于iPSCs重编程研究，其中X染色体状态是影响我们对表观遗传重塑理解的一个新因素。

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引用次数: 3

Involvement of Epigenetic Promoter DNA Methylation of miR-124 in the Pathogenesis of HIV-1-Associated Neurocognitive Disorders. miR-124的表观遗传启动子DNA甲基化参与hiv -1相关神经认知障碍的发病机制

IF 2.2 Q3 Biochemistry, Genetics and Molecular Biology

Epigenetics Insights

Pub Date : 2018-10-14 eCollection Date: 2018-01-01 DOI: 10.1177/2516865718806904

Shilpa Buch, Palsamy Periyasamy, Minglei Guo

Despite the efficacy of combination antiretroviral therapy (cART) in controlling viremia, the central nervous system (CNS) continues to harbor viral reservoirs. The persistence of low-level virus replication leads to the accumulation of early viral proteins, including HIV-1 Transactivator of transcription (HIV-1 Tat) protein. Based on the premise that cART does not impact levels of HIV-1 Tat, and since the CNS is inaccessible to the cART regimens, HIV-1-Tat-mediated neuroinflammation has been implicated as an underlying mediator of HIV-1-associated neurocognitive disorders (HAND). The mechanism(s) underlying the pathogenesis of HAND, however, remain less understood. Understanding the epigenetic/molecular mechanism(s) by which viral proteins such as HIV-1 Tat activate microglia is thus of paramount importance. The study published by Periyasamy et al provides new mechanistic insights into the role of HIV-1-Tat-mediated DNA methylation of miR-124 promoter in regulating microglial activation via the MECP2-STAT3 signaling axis. Furthermore, the authors have also reported that exposure of mouse primary microglial cells to HIV-1 Tat notably increased DNA methylation of primary miR-124-1 and primary miR-124-2 promoters (with no change in primary miR-124-3), resulting in turn to downregulated expression of both primary miR-124-1 and primary miR-124-2 as well as mature miR-124 in mouse primary microglial cells. The authors also examined the involvement of MECP2-STAT3 signaling in HIV-1-Tat-mediated microglial activation. Based on these novel findings, it is evident that dysregulation of miR-124 is involved in the pathogenesis of HAND and that restoration of miR-124 could serve as an adjunctive treatment for dampening neuroinflammation associated with HAND.

尽管抗逆转录病毒联合治疗(cART)在控制病毒血症方面有疗效，但中枢神经系统(CNS)仍然存在病毒库。持续的低水平病毒复制导致早期病毒蛋白的积累，包括HIV-1转录反激活因子(HIV-1 Tat)蛋白。基于cART不影响HIV-1 Tat水平的前提，并且由于cART方案无法进入中枢神经系统，HIV-1 Tat介导的神经炎症被认为是HIV-1相关神经认知障碍(HAND)的潜在介质。然而，HAND的发病机制尚不清楚。因此，了解病毒蛋白(如HIV-1 Tat)激活小胶质细胞的表观遗传/分子机制至关重要。Periyasamy等人发表的这项研究为hiv -1- tat介导的miR-124启动子DNA甲基化在通过MECP2-STAT3信号轴调节小胶质细胞激活中的作用提供了新的机制见解。此外，作者还报道，小鼠原代小胶质细胞暴露于HIV-1显著增加了原代miR-124-1和原代miR-124-2启动子的DNA甲基化(原代miR-124-3没有变化)，导致小鼠原代小胶质细胞中原代miR-124-1和原代miR-124-2以及成熟miR-124的表达下调。作者还研究了MECP2-STAT3信号在hiv -1- tat介导的小胶质细胞激活中的作用。基于这些新发现，很明显miR-124的失调参与了HAND的发病机制，miR-124的恢复可以作为一种辅助治疗来抑制与HAND相关的神经炎症。

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引用次数: 4

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