A Multistate Toggle Switch Defines Fungal Cell Fates and Is Regulated by Synergistic Genetic Cues.
A Multistate Toggle Switch Defines Fungal Cell Fates and Is Regulated by Synergistic Genetic Cues.
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DOI：
10.1371/journal.pgen.1006353
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发表时间：
2016-10
期刊：
影响因子：
4.5
通讯作者：
Bennett RJ
中科院分区：
文献类型：
--
作者：
Anderson MZ;Porman AM;Wang N;Mancera E;Huang D;Cuomo CA;Bennett RJ
可遗传的表观遗传变化是细胞分化成不同细胞类型的能力的基础。在这里，我们证明了真菌病原体热带假丝酵母表现出多能性，在三种细胞状态之间进行随机和可逆的切换。这三种细胞状态表现出独特的细胞形态、生长速率和全局基因表达谱。遗传分析确定了在调节细胞分化中起关键作用的六种转录因子。特别是，我们表明，强制表达的Wor1或Efg1转录因子可用于操纵所有三种细胞状态之间的转换。提出了一种三稳态模型，其中Wor1和Efg1是自激活但相互拮抗的转录因子，从而形成对称的自激活拨动开关。我们明确地测试了这个模型，并表明，异位表达的WOR1可以诱导白色到混合到不透明的切换，而异位表达的EFG1驱动切换在相反的方向，从不透明到混合到白色细胞状态。我们还解决了诱导细胞状态的稳定性，并证明了稳定的分化事件需要异位基因表达与基于染色质的线索相结合。因此，这些研究通过实验测试了多态稳定性模型，并证明转录电路与基于染色质的变化协同作用，以驱动细胞状态转换。我们还建立了密切的机制之间的平行表型转换在单细胞真菌和干细胞重编程过程中的细胞命运的决定。不同细胞类型的形成伴随着多细胞生物的发育，并增加了单细胞物种的种群水平多样性。在这两种情况下，二进制单元命运决定通常由拨动开关决定，其中两个主调节器竞争以定义两种可能的单元状态之一。然而，由于缺乏实验上易处理的系统，对多状态转换知之甚少。在这里，我们证明了真菌病原体热带假丝酵母经历了三个稳定的细胞状态之间的可逆和可遗传的转变。我们提出，三稳态是通过对称的自激活拨动开关实现的，并通过两个主转录因子的异位表达来测试该模型。值得注意的是，操纵两个主调节器的表达诱导了三稳态系统中所有六种可能的状态到状态的转变。此外，我们发现，转录诱导状态的稳定遗传只发生在抑制组蛋白去乙酰化酶活性的情况下。总之，这些结果定义了一个三稳态开关的遗传调控，并表明协同遗传线索（一个转录和一个染色质为基础的）驱动表观遗传遗传在单细胞物种。我们还讨论了惊人的相似之处，在酵母细胞的命运决定和调节细胞分化事件在高等真核生物。
Heritable epigenetic changes underlie the ability of cells to differentiate into distinct cell types. Here, we demonstrate that the fungal pathogen Candida tropicalis exhibits multipotency, undergoing stochastic and reversible switching between three cellular states. The three cell states exhibit unique cellular morphologies, growth rates, and global gene expression profiles. Genetic analysis identified six transcription factors that play key roles in regulating cell differentiation. In particular, we show that forced expression of Wor1 or Efg1 transcription factors can be used to manipulate transitions between all three cell states. A model for tristability is proposed in which Wor1 and Efg1 are self-activating but mutually antagonistic transcription factors, thereby forming a symmetrical self-activating toggle switch. We explicitly test this model and show that ectopic expression of WOR1 can induce white-to-hybrid-to-opaque switching, whereas ectopic expression of EFG1 drives switching in the opposite direction, from opaque-to-hybrid-to-white cell states. We also address the stability of induced cell states and demonstrate that stable differentiation events require ectopic gene expression in combination with chromatin-based cues. These studies therefore experimentally test a model of multistate stability and demonstrate that transcriptional circuits act synergistically with chromatin-based changes to drive cell state transitions. We also establish close mechanistic parallels between phenotypic switching in unicellular fungi and cell fate decisions during stem cell reprogramming. Formation of different cell types accompanies development in multicellular organisms and increases population-level diversity in unicellular species. In both instances, binary cell fate decisions are often determined by toggle switches, in which two master regulators compete to define one of two possible cell states. However, much less is known about multistate transitions due to the lack of experimentally tractable systems. Here, we demonstrate that the fungal pathogen Candida tropicalis undergoes reversible and heritable transitions between three stable cell states. We propose that tristability is achieved by a symmetric self-activating toggle switch and test this model by ectopic expression of the two master transcription factors. Significantly, manipulating the expression of the two master regulators induced all six possible state-to-state transitions in the tristable system. Furthermore, we found that stable inheritance of transcriptionally induced states only occurred if combined with inhibition of a histone deacetylase activity. Together, these results define the genetic regulation of a tristable switch and demonstrate that synergistic genetic cues (one transcriptional and one chromatin-based) drive epigenetic inheritance in a unicellular species. We also discuss striking parallels between cell fate decisions in yeast and the regulation of cell differentiation events in higher eukaryotes.
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影响因子：
3.6
作者：
Hnisz D;Schwarzmüller T;Kuchler K
通讯作者：
Kuchler K
影响因子：
64.5
作者：
Junion, Guillaume;Spivakov, Mikhail;Furlong, Eileen E. M.
通讯作者：
Furlong, Eileen E. M.
模因套件：用于发现和搜索的工具。
影响因子：
14.9
作者：
Bailey TL;Boden M;Buske FA;Frith M;Grant CE;Clementi L;Ren J;Li WW;Noble WS
通讯作者：
Noble WS
影响因子：
46.9
作者：
Danwei Huangfu;Osafune, Kenji;Melton, Douglas A.
通讯作者：
Melton, Douglas A.
DOI：
10.1073/pnas.0605270103
发表时间：
2006-08-22
影响因子：
11.1
作者：
Huang, Guanghua;Wang, Huafeng;Liu, Haoping
通讯作者：
Liu, Haoping