Safeguarding Drosophila female germ cell identity depends on an H3K9me3 mini domain guided by a ZAD zinc finger protein.
Safeguarding Drosophila female germ cell identity depends on an H3K9me3 mini domain guided by a ZAD zinc finger protein.
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DOI：
10.1371/journal.pgen.1010568
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发表时间：
2022-12
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影响因子：
4.5
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中科院分区：
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基于 H3K9me3 的基因沉默是一种确保细胞命运的保守策略，但控制这种表观遗传标记谱系特异性安装的机制仍不清楚。在果蝇中，H3K9 甲基化通过沉默谱系不适当的 phf7 转录，在确保雌性生殖细胞命运方面发挥着重要作用。因此，雌性种系中的 phf7 调节提供了一个强大的系统来剖析 H3K9me3 沉积到蛋白质编码基因上的分子机制。在这里，我们利用遗传学研究来鉴定必需的顺式调控元件，发现 H3K9me3 沉积所需的序列在果蝇物种中是保守的。转座因子也会被 H3K9me3 介导的机制沉默。但我们发现 phf7 调节不需要专用的 piRNA 通路组件 piwi、aub、rhino、panx 和 nxf2，这表明 H3K9me3 招募的机制是不同的。最后，我们发现含有 C2H2 锌指蛋白家族的锌指相关结构域 (ZAD) 的一个未表征的成员 IDENTITY CRISIS (IDC; CG4936) 对于 H3K9me3 沉积到 phf7 上是必需的。生殖细胞中idc的丢失会干扰phf7转录调控和H3K9me3沉积，导致异位PHF7蛋白表达。 IDC 的作用可能是直接的，因为它定位于 phf7 基因内的保守域。总的来说，我们的研究结果支持一个模型，在该模型中，IDC 指导 H3K9me3 迷你结构域的序列特异性建立，从而防止意外的女性向男性编程。组织发育和功能依赖于细胞记住其身份。细胞的身份是由它表达和不表达的基因定义的。最近的研究表明，基因可以通过组蛋白 H3 赖氨酸 9 (H3K9me3) 标记的染色质三甲基化来沉默，并且 H3K9me3 介导的基因沉默是确保细胞命运的重要策略。但关于负责 H3K9 甲基化的机制如何找到其靶基因的信息很少。在这里，我们使用果蝇雌性生殖系来探讨这个问题，其中抑制性 H3K9me3 染色质的微型结构域通过沉默 phf7（一种通常在雄性生殖细胞中表达的基因）来确保雌性生殖细胞的命运。转座元件也被 H3K9me3 微型结构域沉默，但我们发现参与此过程的蛋白质并不是 phf7 沉默所必需的。相反，我们发现沉默需要一种以前未表征的蛋白质，我们将其命名为“身份危机”。我们的工作提供了证据，证明身份危机指导 H3K9 甲基化机器在 phf7 基因座上构建一个迷你结构域。我们的结果为细胞如何通过沉默细胞类型不适当的基因来保护其身份提供了新的线索，更具体地说，这些基因是如何被沉默机制识别的。
H3K9me3-based gene silencing is a conserved strategy for securing cell fate, but the mechanisms controlling lineage-specific installation of this epigenetic mark remain unclear. In Drosophila, H3K9 methylation plays an essential role in securing female germ cell fate by silencing lineage inappropriate phf7 transcription. Thus, phf7 regulation in the female germline provides a powerful system to dissect the molecular mechanism underlying H3K9me3 deposition onto protein coding genes. Here we used genetic studies to identify the essential cis-regulatory elements, finding that the sequences required for H3K9me3 deposition are conserved across Drosophila species. Transposable elements are also silenced by an H3K9me3-mediated mechanism. But our finding that phf7 regulation does not require the dedicated piRNA pathway components, piwi, aub, rhino, panx, and nxf2, indicates that the mechanisms of H3K9me3 recruitment are distinct. Lastly, we discovered that an uncharacterized member of the zinc finger associated domain (ZAD) containing C2H2 zinc finger protein family, IDENTITY CRISIS (IDC; CG4936), is necessary for H3K9me3 deposition onto phf7. Loss of idc in germ cells interferes with phf7 transcriptional regulation and H3K9me3 deposition, resulting in ectopic PHF7 protein expression. IDC’s role is likely to be direct, as it localizes to a conserved domain within the phf7 gene. Collectively, our findings support a model in which IDC guides sequence-specific establishment of an H3K9me3 mini domain, thereby preventing accidental female-to-male programming. Tissue development and function relies on cells remembering their identity. A cell’s identity is defined by the genes it expresses and those it does not. Recent work has shown that genes can be silenced by trimethylation of histone H3 lysine 9 (H3K9me3) marked chromatin, and that H3K9me3-mediated gene silencing is a vital strategy for securing cell fate. But there is very little information about how the machinery responsible for H3K9 methylation finds its target genes. Here we explore this issue using the Drosophila female germline where a mini domain of repressive H3K9me3 chromatin secures female germ cell fate by silencing phf7, a gene normally expressed in male germ cells. Transposable elements are also silenced by H3K9me3 mini domains, but we find that the proteins involved in this process are not required for phf7 silencing. Instead, we find that silencing requires a previously uncharacterized protein, we have named IDENTITY CRISIS. Our work provides evidence that IDENTITY CRISIS directs the H3K9 methylation machinery to build a mini domain at the phf7 locus. Our results shed new light into how cells safeguard their identity by silencing cell type inappropriate genes, and more specifically how these genes are identified by the silencing machinery.
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影响因子：
--
作者：
VanKuren NW;Vibranovski MD
通讯作者：
Vibranovski MD
H3K9ME3依赖性异染色质：细胞命运变化的屏障。
DOI：
10.1016/j.tig.2015.11.001
发表时间：
2016-01
期刊：
Trends in genetics : TIG
影响因子：
--
作者：
Becker JS;Nicetto D;Zaret KS
通讯作者：
Zaret KS
影响因子：
30.8
作者：
Jiang Y;Loh YE;Rajarajan P;Hirayama T;Liao W;Kassim BS;Javidfar B;Hartley BJ;Kleofas L;Park RB;Labonte B;Ho SM;Chandrasekaran S;Do C;Ramirez BR;Peter CJ;C W JT;Safaie BM;Morishita H;Roussos P;Nestler EJ;Schaefer A;Tycko B;Brennand KJ;Yagi T;Shen L;Akbarian S
通讯作者：
Akbarian S
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
7.7
作者：
Baumgartner L;Handler D;Platzer SW;Yu C;Duchek P;Brennecke J
通讯作者：
Brennecke J