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Hyphal development in Candida albicans requires two temporally linked changes in promoter chromatin for initiation and maintenance.

Lu Y, Su C, Wang A, Liu H - PLoS Biol. (2011)

Bottom Line: Although many regulators have been found involved in hyphal development, the mechanisms of regulating hyphal development and plasticity of dimorphism remain unclear.Maintenance requires promoter recruitment of Hda1 histone deacetylase under reduced Tor1 (target of rapamycin) signaling.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Chemistry, University of California, Irvine, California, United States of America.

ABSTRACT
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.

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A schematic diagram depicting initiation and maintenance of hyphal development.(A) Hyphal development in C. albicans requires two phases of sequential changes in the promoter chromatin of hypha-specific genes. Initiation requires a rapid but temporary disappearance of Nrg1 in response to the activation of the cAMP-PKA pathway, while the duration of hyphal development is under the regulation of the TOR pathway by controlling promoter access to Nrg1 through recruitment of Hda1. Black lines represent active regulatory relationships; grey lines represent relationships that are inactive. Dashed circles represent degraded proteins. (B) Hda1 is recruited only during the time period when Nrg1 is absent. This provides a mechanism for temporal integration of two major nutrient-sensing cell growth pathways in development.
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pbio-1001105-g009: A schematic diagram depicting initiation and maintenance of hyphal development.(A) Hyphal development in C. albicans requires two phases of sequential changes in the promoter chromatin of hypha-specific genes. Initiation requires a rapid but temporary disappearance of Nrg1 in response to the activation of the cAMP-PKA pathway, while the duration of hyphal development is under the regulation of the TOR pathway by controlling promoter access to Nrg1 through recruitment of Hda1. Black lines represent active regulatory relationships; grey lines represent relationships that are inactive. Dashed circles represent degraded proteins. (B) Hda1 is recruited only during the time period when Nrg1 is absent. This provides a mechanism for temporal integration of two major nutrient-sensing cell growth pathways in development.

Mentions: This study shows that the yeast to hyphae morphogenetic switch consists of two temporally related phases of regulation of the promoter chromatin of hypha-specific genes: the first for initiation and the second for maintenance of hyphal development (Figure 9). Initiation requires the cAMP-PKA pathway and maintenance requires reduced Tor1 signaling. A spike of cAMP-PKA activation [10] and release from the inhibition of quorum sensing molecules, such as farnesol, initiate hyphal development by transiently clearing Nrg1 protein. The duration of hyphal development is under the regulation of Tor1 by controlling promoter access to Nrg1 through promoter recruitment of Hda1. Therefore, hyphal maintenance requires active sensing of growth environments. Hyphal cells convert to yeast when nutrients are replete. This provides an underlying mechanism for the plasticity of dimorphism. Importantly, the sustained transcriptional program, as measured by promoter recruitment of Hda1, can only be established during the time period when Nrg1 is absent. This provides a temporal link at the molecular level between the two phases of hyphal development. This is the first example of a temporal integration of two major nutrient-sensing cell growth pathways in development. Temporal restriction in development of multicellular organisms is common. For example, nutritional control of the reproductive status in honeybees is restricted by a critical “decision-making” period in larval development [61]. Our study also provides a mechanism for how a transient signal, such as a cAMP spike, can make a long-lasting impact in transcriptional reprogramming during development. Such control of cellular development by a burst of proliferating signal, followed with sustained action of reduced TOR signaling has been observed for memory T-cell differentiation [62]. The TOR level is also critical for maintaining stem cell homeostasis [63]–[65]. Temporal regulation of cell fate by different signaling pathways is likely common in development of multicellular organisms. Coupling two signaling pathways through the regulation of promoter chromatin provides a unique mechanism.


Hyphal development in Candida albicans requires two temporally linked changes in promoter chromatin for initiation and maintenance.

Lu Y, Su C, Wang A, Liu H - PLoS Biol. (2011)

A schematic diagram depicting initiation and maintenance of hyphal development.(A) Hyphal development in C. albicans requires two phases of sequential changes in the promoter chromatin of hypha-specific genes. Initiation requires a rapid but temporary disappearance of Nrg1 in response to the activation of the cAMP-PKA pathway, while the duration of hyphal development is under the regulation of the TOR pathway by controlling promoter access to Nrg1 through recruitment of Hda1. Black lines represent active regulatory relationships; grey lines represent relationships that are inactive. Dashed circles represent degraded proteins. (B) Hda1 is recruited only during the time period when Nrg1 is absent. This provides a mechanism for temporal integration of two major nutrient-sensing cell growth pathways in development.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3139633&req=5

pbio-1001105-g009: A schematic diagram depicting initiation and maintenance of hyphal development.(A) Hyphal development in C. albicans requires two phases of sequential changes in the promoter chromatin of hypha-specific genes. Initiation requires a rapid but temporary disappearance of Nrg1 in response to the activation of the cAMP-PKA pathway, while the duration of hyphal development is under the regulation of the TOR pathway by controlling promoter access to Nrg1 through recruitment of Hda1. Black lines represent active regulatory relationships; grey lines represent relationships that are inactive. Dashed circles represent degraded proteins. (B) Hda1 is recruited only during the time period when Nrg1 is absent. This provides a mechanism for temporal integration of two major nutrient-sensing cell growth pathways in development.
Mentions: This study shows that the yeast to hyphae morphogenetic switch consists of two temporally related phases of regulation of the promoter chromatin of hypha-specific genes: the first for initiation and the second for maintenance of hyphal development (Figure 9). Initiation requires the cAMP-PKA pathway and maintenance requires reduced Tor1 signaling. A spike of cAMP-PKA activation [10] and release from the inhibition of quorum sensing molecules, such as farnesol, initiate hyphal development by transiently clearing Nrg1 protein. The duration of hyphal development is under the regulation of Tor1 by controlling promoter access to Nrg1 through promoter recruitment of Hda1. Therefore, hyphal maintenance requires active sensing of growth environments. Hyphal cells convert to yeast when nutrients are replete. This provides an underlying mechanism for the plasticity of dimorphism. Importantly, the sustained transcriptional program, as measured by promoter recruitment of Hda1, can only be established during the time period when Nrg1 is absent. This provides a temporal link at the molecular level between the two phases of hyphal development. This is the first example of a temporal integration of two major nutrient-sensing cell growth pathways in development. Temporal restriction in development of multicellular organisms is common. For example, nutritional control of the reproductive status in honeybees is restricted by a critical “decision-making” period in larval development [61]. Our study also provides a mechanism for how a transient signal, such as a cAMP spike, can make a long-lasting impact in transcriptional reprogramming during development. Such control of cellular development by a burst of proliferating signal, followed with sustained action of reduced TOR signaling has been observed for memory T-cell differentiation [62]. The TOR level is also critical for maintaining stem cell homeostasis [63]–[65]. Temporal regulation of cell fate by different signaling pathways is likely common in development of multicellular organisms. Coupling two signaling pathways through the regulation of promoter chromatin provides a unique mechanism.

Bottom Line: Although many regulators have been found involved in hyphal development, the mechanisms of regulating hyphal development and plasticity of dimorphism remain unclear.Maintenance requires promoter recruitment of Hda1 histone deacetylase under reduced Tor1 (target of rapamycin) signaling.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Chemistry, University of California, Irvine, California, United States of America.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus