A GATA transcription factor recruits Hda1 in response to reduced Tor1 signaling to establish a hyphal chromatin state in Candida albicans.
A GATA transcription factor recruits Hda1 in response to reduced Tor1 signaling to establish a hyphal chromatin state in Candida albicans.
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DOI：
10.1371/journal.ppat.1002663
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Liu H
中科院分区：
文献类型：
--
作者：
Lu Y;Su C;Liu H
白色念珠菌是免疫功能低下个体的重要条件致病真菌。一个关键的毒力属性是其形态发生可塑性。菌丝发育需要启动子染色质的两个时间上相关的变化，这是顺序调节的cAMP/PKA途径激活后暂时清除转录抑制剂Nrg 1和启动子招募组蛋白脱乙酰酶Hda 1下减少Tor 1信号。时间连接的分子机制以及与Tor 1信号的联系尚不清楚。在这里，通过正向遗传筛选，我们报告的加塔家族转录因子Brg 1的识别的因素，招聘Hda 1的菌丝生长过程中的菌丝特异性基因的启动子。BRG 1表达需要去除Nrg 1和亚生长抑制水平的雷帕霉素;因此，它是Tor 1信号传导的敏感读数。有趣的是，菌丝特异性基因的启动子在酵母细胞中不能接近Brg 1。此外，Brg 1的异位表达不能诱导菌丝，但可以维持菌丝的发育。菌丝特异性启动子的核小体定位显示，Nrg 1结合位点位于酵母细胞的核小体自由区，而Brg 1结合位点被核小体占据。在菌丝起始过程中，核小体解体暴露了两种调节剂的结合位点。在菌丝伸长过程中，Brg 1介导的Hda 1募集导致核小体重新定位和Nrg 1结合位点的闭塞。我们认为，核小体的重新定位是酵母菌丝过渡的潜在机制。菌丝特异性调节子Ume 6是Brg 1的关键下游靶标，在Brg 1之后作为菌丝转录程序的内置正反馈调节子发挥功能，以维持菌丝发育。随着Nrg 1和Brg 1水平的动态和敏感性控制的两个主要的细胞生长途径，在酵母菌到菌丝的过渡过程中的核小体定位的时间变化提供了一种机制，信号整合和细胞命运的规范。这种机制可能在开发中广泛使用。 念珠菌属是健康个体肠道微生物菌群的一部分，但当宿主的免疫系统受到抑制时，它可以传播并引起全身性疾病。其作为酵母菌和菌丝生长以响应环境信号的能力是其主要的毒力属性。菌丝发育需要在cAMP/PKA激活后暂时清除转录抑制剂Nrg 1，以启动组蛋白脱乙酰酶Hda 1，并在减少的Tor 1信号传导下启动子募集以维持。在这里，我们表明，在菌丝起始时，Nrg 1消失了，表达的加塔家族转录因子Brg 1下减少Tor 1信号被激活。积累的Brg 1招募Hda 1菌丝启动子重新定位核小体，导致Nrg 1结合位点的阻塞和持续的菌丝发育。核小体在酵母-菌丝转化过程中的重新定位为细胞外信号的时间整合和细胞命运的规范提供了一种机制。菌丝特异性转录因子Ume 6功能Brg 1后，在这一系列的前馈调节菌丝发育。由于Nrg 1或Ume 6的错误调节会导致毒力改变，而Brg 1调节Nrg 1的可及性和Ume 6的转录，我们的研究结果应该提供一个更好的了解念珠菌如何控制其形态程序在不同的主机生态位存在作为一种寄生虫和病原体。
Candida albicans is an important opportunistic fungal pathogen of immunocompromised individuals. One critical virulence attribute is its morphogenetic plasticity. Hyphal development requires two temporally linked changes in promoter chromatin, which is sequentially regulated by temporarily clearing the transcription inhibitor Nrg1 upon activation of the cAMP/PKA pathway and promoter recruitment of the histone deacetylase Hda1 under reduced Tor1 signaling. Molecular mechanisms for the temporal connection and the link to Tor1 signaling are not clear. Here, through a forward genetic screen, we report the identification of the GATA family transcription factor Brg1 as the factor that recruits Hda1 to promoters of hypha-specific genes during hyphal elongation. BRG1 expression requires both the removal of Nrg1 and a sub-growth inhibitory level of rapamycin; therefore, it is a sensitive readout of Tor1 signaling. Interestingly, promoters of hypha-specific genes are not accessible to Brg1 in yeast cells. Furthermore, ectopic expression of Brg1 cannot induce hyphae, but can sustain hyphal development. Nucleosome mapping of a hypha-specific promoter shows that Nrg1 binding sites are in nucleosome free regions in yeast cells, whereas Brg1 binding sites are occupied by nucleosomes. Nucleosome disassembly during hyphal initiation exposes the binding sites for both regulators. During hyphal elongation, Brg1-mediated Hda1 recruitment causes nucleosome repositioning and occlusion of Nrg1 binding sites. We suggest that nucleosome repositioning is the underlying mechanism for the yeast-hyphal transition. The hypha-specific regulator Ume6 is a key downstream target of Brg1 and functions after Brg1 as a built-in positive feedback regulator of the hyphal transcriptional program to sustain hyphal development. With the levels of Nrg1 and Brg1 dynamically and sensitively controlled by the two major cellular growth pathways, temporal changes in nucleosome positioning during the yeast-to-hypha transition provide a mechanism for signal integration and cell fate specification. This mechanism is likely used broadly in development. Candida is part of the gut microflora in healthy individuals, but can disseminate and cause systemic disease when the host's immune system is suppressed. Its ability to grow as yeast and hyphae in response to environmental cues is a major virulence attribute. Hyphal development requires temporary clearing of the transcription inhibitor Nrg1 upon activation of cAMP/PKA for initiation and promoter recruitment of the histone deacetylase Hda1 under reduced Tor1 signaling for maintenance. Here, we show that, during hyphal initiation when Nrg1 is gone, expression of the GATA family transcription factor Brg1 is activated under reduced Tor1 signaling. Accumulated Brg1 recruits Hda1 to hyphal promoters to reposition nucleosomes, leading to obstruction of Nrg1 binding sites and sustained hyphal development. The nucleosome repositioning during the yeast-hyphal transition provides a mechanism for temporal integration of extracellular signals and cell-fate specification. The hypha-specific transcription factor Ume6 functions after Brg1 in this succession of feed-forward regulation of hyphal development. Since misregulation of either Nrg1 or Ume6 causes altered virulence, and Brg1 regulates both Nrg1 accessibility and Ume6 transcription, our findings should provide a better understanding of how Candida controls its morphological program in different host niches to exist as a commensal and a pathogen.
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