Hyphal development in Candida albicans requires two temporally linked changes in promoter chromatin for initiation and maintenance.
Hyphal development in Candida albicans requires two temporally linked changes in promoter chromatin for initiation and maintenance.
复制标题
DOI：
10.1371/journal.pbio.1001105
复制
发表时间：
2011-07
期刊：
影响因子：
9.8
通讯作者：
Liu H
中科院分区：
文献类型：
--
作者：
Lu Y;Su C;Wang A;Liu H
表型可塑性在发育过程中很常见。对于白色念珠菌，人类侵袭性真菌感染的最常见原因，形态可塑性是其定义特征，是其发病机制的关键。与其他主要以酵母或菌丝形式存在的真菌病原体不同，白色念珠菌能够在酵母和菌丝生长形式之间可逆地切换，以响应环境线索。虽然已经发现许多调控因子参与菌丝发育，但调控菌丝发育和二态性可塑性的机制尚不清楚。在这里，我们表明菌丝发育涉及菌丝特异性基因启动子染色质的两个顺序调节。起始需要通过激活cAMP-PKA途径快速但暂时地消除菌丝形态发生的Nrg1转录抑制因子。维持需要在Tor1（雷帕霉素的靶标）信号减少的情况下募集Hda1组蛋白去乙酰化酶启动子。Hda1使NuA4组蛋白乙酰转移酶模块的一个亚基去乙酰化，导致NuA4乙酰转移酶模块被移除，并阻断Nrg1进入菌丝特异性基因启动子的通路。启动子募集Hda1维持菌丝只发生在Nrg1消失的时期。cAMP-PKA通路的激活和Tor1信号的减少对菌丝发育的序贯调控为二态性的可塑性和白色念珠菌在发病过程中如何适应不同的宿主环境提供了分子机制。这种通过不同信号通路对启动子染色质进行的时间连锁调控，为在发育和细胞命运规范过程中整合多种信号提供了一种独特的机制。许多生物体能够根据环境的变化改变它们的表型，这种现象被称为可塑性。白色念珠菌是人类主要的机会性真菌病原体，可以在酵母（球形）和菌丝（丝状）生长形式之间经历可逆的形态变化，以响应环境线索。这种形态的可塑性对其在宿主体内的发病和存活至关重要。在这项研究中，我们发现菌丝的发育是由两种主要的营养感知细胞生长途径启动和维持的，这两种途径通过去除转录抑制因子Nrg1提供的抑制来起作用。起始需要通过激活camp依赖性蛋白激酶a途径使Nrg1快速但暂时消失，而维持需要在雷帕霉素（TOR）激酶靶信号减少的条件下招募到Hda1组蛋白去乙酰化酶的启动子，从而导致染色质重塑，阻止Nrg1进入菌丝特异性基因的启动子。我们观察到Hda1向启动子的募集只发生在Nrg1缺失的时间窗口内。这种通过不同信号通路对启动子染色质的时间连锁调控提供了一种独特的机制，可以整合多种信号来调控发育过程中的基因表达和表型可塑性以及细胞命运规范。
Phenotypic plasticity is common in development. For Candida albicans, the most common cause of invasive fungal infections in humans, morphological plasticity is its defining feature and is critical for its pathogenesis. Unlike other fungal pathogens that exist primarily in either yeast or hyphal forms, C. albicans is able to switch reversibly between yeast and hyphal growth forms in response to environmental cues. Although many regulators have been found involved in hyphal development, the mechanisms of regulating hyphal development and plasticity of dimorphism remain unclear. Here we show that hyphal development involves two sequential regulations of the promoter chromatin of hypha-specific genes. Initiation requires a rapid but temporary disappearance of the Nrg1 transcriptional repressor of hyphal morphogenesis via activation of the cAMP-PKA pathway. Maintenance requires promoter recruitment of Hda1 histone deacetylase under reduced Tor1 (target of rapamycin) signaling. Hda1 deacetylates a subunit of the NuA4 histone acetyltransferase module, leading to eviction of the NuA4 acetyltransferase module and blockage of Nrg1 access to promoters of hypha-specific genes. Promoter recruitment of Hda1 for hyphal maintenance happens only during the period when Nrg1 is gone. The sequential regulation of hyphal development by the activation of the cAMP-PKA pathway and reduced Tor1 signaling provides a molecular mechanism for plasticity of dimorphism and how C. albicans adapts to the varied host environments in pathogenesis. Such temporally linked regulation of promoter chromatin by different signaling pathways provides a unique mechanism for integrating multiple signals during development and cell fate specification. Many organisms are able to change their phenotype in response to changes in the environment, a phenomenon referred to as plasticity. Candida albicans, a major opportunistic fungal pathogen of humans, can undergo reversible morphological changes between yeast (spherical) and hyphal (filamentous) forms of growth in response to environmental cues. This morphological plasticity is essential for its pathogenesis and survival in its hosts. In this study, we show that hyphal development is initiated and maintained by two major nutrient-sensing cellular growth pathways that act by removing the inhibition provided by the transcriptional repressor Nrg1. While initiation requires a rapid but temporary disappearance of Nrg1 via activation of the cAMP-dependent protein kinase A pathway, maintenance requires the recruitment to promoters of the Hda1 histone deacetylase under conditions of reduced signaling by the target of rapamycin (TOR) kinase, leading to chromatin remodeling that blocks Nrg1 access to the promoters of hypha-specific genes. We observed that recruitment of Hda1 to promoters happens only during the time window when Nrg1 is absent. Such temporally linked regulation of promoter chromatin by different signaling pathways provides a unique mechanism for integrating multiple signals in the regulation of gene expression and phenotypic plasticity during development and cell fate specification.
登录
查看更多内容
影响因子：
64.5
作者：
Hobbs RM;Seandel M;Falciatori I;Rafii S;Pandolfi PP
通讯作者：
Pandolfi PP
影响因子：
--
作者：
Bauer, Janine;Wendland, Juergen
通讯作者：
Wendland, Juergen
影响因子：
64.8
作者：
Araki, Koichi;Turner, Alexandra P.;Shaffer, Virginia Oliva;Gangappa, Shivaprakash;Keller, Susanne A.;Bachmann, Martin F.;Larsen, Christian P.;Ahmed, Rafi
通讯作者：
Ahmed, Rafi
影响因子：
4.9
作者：
Cruz, MC;Goldstein, AL;Heitman, J
通讯作者：
Heitman, J
影响因子：
3.3
作者：
Cutler, NS;Pan, XW;Cardenas, ME
通讯作者：
Cardenas, ME