scholarly journals Nucleosome Assembly Factors CAF-1 and HIR Modulate Epigenetic Switching Frequencies in an H3K56 Acetylation-Associated Manner in Candida albicans

2013 ◽  
Vol 12 (4) ◽  
pp. 591-603 ◽  
Author(s):  
John S. Stevenson ◽  
Haoping Liu
Keyword(s):  
Cell Fate ◽  
Stress Responses ◽  
Protein Complexes ◽  
Ectopic Expression ◽  
Cell Types ◽  
Nucleosome Assembly ◽  
Content Type ◽  
Histone Gene Expression ◽  
H3k56 Acetylation ◽  
Increased Sensitivity

ABSTRACT CAF-1 and HIR are highly conserved histone chaperone protein complexes that function in the assembly of nucleosomes onto chromatin. CAF-1 is characterized as having replication-coupled nucleosome activity, whereas the HIR complex can assemble nucleosomes independent of replication. Histone H3K56 acetylation, controlled by the acetyltransferase Rtt109 and deacetylase Hst3, also plays a significant role in nucleosome assembly. In this study, we generated a set of deletion mutants to genetically characterize pathway-specific and overlapping functions of CAF-1 and HIR in C. albicans . Their roles in epigenetic maintenance of cell type were examined by using the white-opaque switching system in C. albicans . We show that CAF-1 and HIR play conserved roles in UV radiation recovery, repression of histone gene expression, correct chromosome segregation, and stress responses. Unique to C. albicans , the cac2Δ/Δ mutant shows increased sensitivity to the Hst3 inhibitor nicotinamide, while the rtt109Δ/Δ cac2Δ/Δ and hir1Δ/Δ cac2Δ/Δ mutants are resistant to nicotinamide. CAF-1 plays a major role in maintaining cell types, as the cac2Δ/Δ mutant exhibited increased switching frequencies in both directions and switched at a high frequency to opaque in response to nicotinamide. Like the rtt109Δ/Δ mutant, the hir1Δ/Δ cac2Δ/Δ double mutant is defective in maintaining the opaque cell fate and blocks nicotinamide-induced opaque formation, and the defects are suppressed by ectopic expression of the master white-opaque regulator Wor1. Our data suggest an overlapping function of CAF-1 and HIR in epigenetic regulation of cell fate determination in an H3K56 acetylation-associated manner.

scholarly journals The genetic basis for the evolution of soma: mechanistic evidence for the co-option of a stress-induced gene into a developmental master regulator

2020 ◽  
Vol 287 (1940) ◽  
pp. 20201414
Author(s):  
Stephan G. König ◽  
Aurora M. Nedelcu
Keyword(s):  
Cell Fate ◽  
Stress Responses ◽  
Regulatory Gene ◽  
Somatic Cells ◽  
Cell Types ◽  
Volvox Carteri ◽  
Developmentally Regulated ◽  
Evolutionary Origins ◽  
Increased Sensitivity ◽  
Multicellular Organisms

In multicellular organisms with specialized cells, the most significant distinction among cell types is between reproductive (germ) cells and non-reproductive/somatic cells (soma). Although soma contributed to the marked increase in complexity of many multicellular lineages, little is known about its evolutionary origins. We have previously suggested that the evolution of genes responsible for the differentiation of somatic cells involved the co-option of life history trade-off genes that in unicellular organisms enhanced survival at a cost to immediate reproduction. In the multicellular green alga, Volvox carteri , cell fate is established early in development by the differential expression of a master regulatory gene known as regA . A closely related RegA -Like Sequence ( RLS1 ) is present in its single-celled relative, Chlamydomonas reinhardtii . RLS1 is expressed in response to stress, and we proposed that an environmentally induced RLS1 -like gene was co-opted into a developmental pathway in the lineage leading to V. carteri . However, the exact evolutionary scenario responsible for the postulated co-option event remains to be determined. Here, we show that in addition to being developmentally regulated, regA can also be induced by environmental cues, indicating that regA has maintained its ancestral regulation. We also found that the absence of a functional RegA protein confers increased sensitivity to stress, consistent with RegA having a direct or indirect role in stress responses. Overall, this study (i) provides mechanistic evidence for the co-option of an environmentally induced gene into a major developmental regulator, (ii) supports the view that major morphological innovations can evolve via regulatory changes and (iii) argues for the role of stress in the evolution of multicellular complexity.

scholarly journals The ClpCP Complex Modulates Respiratory Metabolism inStaphylococcus aureusand Is Regulated in a SrrAB-Dependent Manner

2019 ◽  
Vol 201 (15) ◽  
Author(s):  
Ameya A. Mashruwala ◽  
Brian J. Eilers ◽  
Amanda L. Fuchs ◽  
Javiera Norambuena ◽  
Carly A. Earle ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Energy Metabolism ◽  
Energy Homeostasis ◽  
Protein Complexes ◽  
Present Report ◽  
Bacterial Pathogen ◽  
Dependent Manner ◽  
Content Type ◽  
Fermentative Growth ◽  
Increased Sensitivity

ABSTRACTThestaphylococcalrespiratoryregulator (SrrAB) modulates energy metabolism inStaphylococcus aureus. Studies have suggested that regulated protein catabolism facilitates energy homeostasis. Regulated proteolysis inS. aureusis achieved through protein complexes composed of a peptidase (ClpQ or ClpP) in association with an AAA+family ATPase (typically, ClpC or ClpX). In the present report, we tested the hypothesis that SrrAB regulates a Clp complex to facilitate energy homeostasis inS. aureus. Strains deficient in one or more Clp complexes were attenuated for growth in the presence of puromycin, which causes enrichment of misfolded proteins. A ΔsrrABstrain had increased sensitivity to puromycin. Epistasis experiments suggested that the puromycin sensitivity phenotype of the ΔsrrABstrain was a result of decreased ClpC activity. Consistent with this, transcriptional activity ofclpCwas decreased in the ΔsrrABmutant, and overexpression ofclpCsuppressed the puromycin sensitivity of the ΔsrrABstrain. We also found that ClpC positively influenced respiration and that it did so upon association with ClpP. In contrast, ClpC limited fermentative growth, while ClpP was required for optimal fermentative growth. Metabolomics studies demonstrated that intracellular metabolic profiles of the ΔclpCand ΔsrrABmutants were distinct from those of the wild-type strain, supporting the notion that both ClpC and SrrAB affect central metabolism. We propose a model wherein SrrAB regulates energy homeostasis, in part, via modulation of regulated proteolysis.IMPORTANCEOxygen is used as a substrate to derive energy by the bacterial pathogenStaphylococcus aureusduring infection; however,S. aureuscan also grow fermentatively in the absence of oxygen. To successfully cause infection,S. aureusmust tailor its metabolism to take advantage of respiratory activity. Different proteins are required for growth in the presence or absence of oxygen; therefore, when cells transition between these conditions, several proteins would be expected to become unnecessary. In this report, we show that regulated proteolysis is used to modulate energy metabolism inS. aureus. We report that the ClpCP protein complex is involved in specifically modulating aerobic respiratory growth but is dispensable for fermentative growth.

scholarly journals Activation of Toxin-Antitoxin System Toxins Suppresses Lethality Caused by the Loss of σEin Escherichia coli

2015 ◽  
Vol 197 (14) ◽  
pp. 2316-2324 ◽  
Author(s):  
Yasushi Daimon ◽  
Shin-ichiro Narita ◽  
Yoshinori Akiyama
Keyword(s):  
Escherichia Coli ◽  
Stress Responses ◽  
Ectopic Expression ◽  
Growth Media ◽  
Content Type ◽  
E Coli ◽  
Envelope Stress ◽  
Genes Encoding ◽  
Σ Factor ◽  
Mutant Forms

ABSTRACTσE, an alternative σ factor that governs a major signaling pathway in envelope stress responses in Gram-negative bacteria, is essential for growth ofEscherichia colinot only under stressful conditions, such as elevated temperature, but also under normal laboratory conditions. A mutational inactivation of thehicBgene has been reported to suppress the lethality caused by the loss of σE.hicBencodes the antitoxin of the HicA-HicB toxin-antitoxin (TA) system; overexpression of the HicA toxin, which exhibits mRNA interferase activity, causes cleavage of mRNAs and an arrest of cell growth, while simultaneous expression of HicB neutralizes the toxic effects of overproduced HicA. To date, however, how the loss of HicB rescues the cell lethality in the absence of σEand, more specifically, whether HicA is involved in this process remain unknown. Here we showed that simultaneous disruption ofhicAabolished suppression of the σEessentiality in the absence ofhicB, while ectopic expression of wild-type HicA, but not that of its mutant forms without mRNA interferase activity, restored the suppression. Furthermore, HicA and two other mRNA interferase toxins, HigB and YafQ, suppressed the σEessentiality even in the presence of chromosomally encoded cognate antitoxins when these toxins were overexpressed individually. Interestingly, when the growth media were supplemented with low levels of antibiotics that are known to activate toxins,E. colicells with no suppressor mutations grew independently of σE. Taken together, our results indicate that the activation of TA system toxins can suppress the σEessentiality and affect the extracytoplasmic stress responses.IMPORTANCEσEis an alternative σ factor involved in extracytoplasmic stress responses. Unlike other alternative σ factors, σEis indispensable for the survival ofE. colieven under unstressed conditions, although the exact reason for its essentiality remains unknown. Toxin-antitoxin (TA) systems are widely distributed in prokaryotes and are composed of two adjacent genes, encoding a toxin that exerts harmful effects on the toxin-producing bacterium itself and an antitoxin that neutralizes the cognate toxin. Curiously, it is known that inactivation of an antitoxin rescues the σEessentiality, suggesting a connection between TA systems and σEfunction. We demonstrate here that toxin activation is necessary for this rescue and suggest the possible involvement of TA systems in extracytoplasmic stress responses.

scholarly journals Translational control of C/EBPα and C/EBPβ isoform expression

2000 ◽  
Vol 14 (15) ◽  
pp. 1920-1932 ◽  
Author(s):  
Cor F. Calkhoven ◽  
Christine Müller ◽  
Achim Leutz
Keyword(s):  
Cell Fate ◽  
Translation Initiation ◽  
Translational Control ◽  
Ectopic Expression ◽  
Cell Types ◽  
Upstream Open Reading Frame ◽  
Reading Frame ◽  
Initiation Of Translation ◽  
Isoform Expression ◽  
Differentiation And Proliferation

Transcription factors derived from CCAAT/enhancer binding protein (C/EBP)α and C/EBPβ genes control differentiation and proliferation in a number of cell types. Various C/EBP isoforms arise from unique C/EBPβ and C/EBPα mRNAs by differential initiation of translation. These isoforms retain different parts of the amino terminus and therefore display different functions in gene regulation and proliferation control. We show that PKR and mTOR signaling pathways control the ratio of C/EBP isoform expression through the eukaryotic translation initiation factors eIF-2α and eIF-4E, respectively. An evolutionary conserved upstream open reading frame in C/EBPα and C/EBPβ mRNAs is a prerequisite for regulated initiation from the different translation initiation sites and integrates translation factor activity. Deregulated translational control leading to aberrant C/EBPα and C/EBPβ isoform expression or ectopic expression of truncated isoforms disrupts terminal differentiation and induces a transformed phenotype in 3T3-L1 cells. Our results demonstrate that the translational controlled ratio of C/EBPα and C/EBPβ isoform expression determines cell fate.

scholarly journals Developmental Cell Fate and Virulence Are Linked to Trehalose Homeostasis in Cryptococcus neoformans

2014 ◽  
Vol 13 (9) ◽  
pp. 1158-1168 ◽  
Author(s):  
Michael R. Botts ◽  
Mingwei Huang ◽  
Regen K. Borchardt ◽  
Christina M. Hull
Keyword(s):  
Cryptococcus Neoformans ◽  
Cell Fate ◽  
Spore Germination ◽  
Molecular Genetic ◽  
Cell Types ◽  
Mammalian Host ◽  
Spore Viability ◽  
Content Type ◽  
Cell Fate Decisions ◽  
Metabolic Adaptations

ABSTRACTAmong pathogenic environmental fungi, spores are thought to be infectious particles that germinate in the host to cause disease. The meningoencephalitis-causing yeastCryptococcus neoformansis found ubiquitously in the environment and sporulates in response to nutrient limitation. While the yeast form has been studied extensively, relatively little is known about spore biogenesis, and spore germination has never been evaluated at the molecular level. Using genome transcript analysis of spores and molecular genetic approaches, we discovered that trehalose homeostasis plays a key role in regulating sporulation ofC. neoformans, is required for full spore viability, and influences virulence. Specifically, we found that genes involved in trehalose metabolism, including a previously uncharacterized secreted trehalase (NTH2), are highly overrepresented in dormant spores. Deletion of the two predicted trehalases in theC. neoformansgenome,NTH1andNTH2, resulted in severe defects in spore production, a decrease in spore germination, and an increase in the production of alternative developmental structures. This shift in cell types suggests that trehalose levels modulate cell fate decisions during sexual development. We also discovered that deletion of theNTH2trehalase results in hypervirulence in a murine model of infection. Taken together, these data show that the metabolic adaptations that allow this fungus to proliferate ubiquitously in the environment play unexpected roles in virulence in the mammalian host and highlight the complex interplay among the processes of metabolism, development, and pathogenesis.

scholarly journals Two transcription factors, Pou4f2 and Isl1, are sufficient to specify the retinal ganglion cell fate

2015 ◽  
Vol 112 (13) ◽  
pp. E1559-E1568 ◽  
Author(s):  
Fuguo Wu ◽  
Tadeusz J. Kaczynski ◽  
Santhosh Sethuramanujam ◽  
Renzhong Li ◽  
Varsha Jain ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Fate ◽  
Ganglion Cells ◽  
Ectopic Expression ◽  
Cell Types ◽  
Retinal Cell ◽  
Retinal Ganglion ◽  
Pou Domain ◽  
Gene Enhancer ◽  
Gene Regulatory

As with other retinal cell types, retinal ganglion cells (RGCs) arise from multipotent retinal progenitor cells (RPCs), and their formation is regulated by a hierarchical gene-regulatory network (GRN). Within this GRN, three transcription factors—atonal homolog 7 (Atoh7), POU domain, class 4, transcription factor 2 (Pou4f2), and insulin gene enhancer protein 1 (Isl1)—occupy key node positions at two different stages of RGC development. Atoh7 is upstream and is required for RPCs to gain competence for an RGC fate, whereas Pou4f2 and Isl1 are downstream and regulate RGC differentiation. However, the genetic and molecular basis for the specification of the RGC fate, a key step in RGC development, remains unclear. Here we report that ectopic expression of Pou4f2 and Isl1 in the Atoh7-null retina using a binary knockin-transgenic system is sufficient for the specification of the RGC fate. The RGCs thus formed are largely normal in gene expression, survive to postnatal stages, and are physiologically functional. Our results indicate that Pou4f2 and Isl1 compose a minimally sufficient regulatory core for the RGC fate. We further conclude that during development a core group of limited transcription factors, including Pou4f2 and Isl1, function downstream of Atoh7 to determine the RGC fate and initiate RGC differentiation.

scholarly journals High-Temperature Protein G Is an Essential Virulence Factor of Leptospira interrogans

2013 ◽  
Vol 82 (3) ◽  
pp. 1123-1131 ◽  
Author(s):  
Amy M. King ◽  
Gabriela Pretre ◽  
Thanatchaporn Bartpho ◽  
Rasana W. Sermswan ◽  
Claudia Toma ◽  
...  
Keyword(s):  
Virulence Factor ◽  
Stress Responses ◽  
Vaccine Development ◽  
Bacterial Species ◽  
Insertion Mutant ◽  
Leptospira Interrogans ◽  
Hamster Model ◽  
Content Type ◽  
Transposon Insertion ◽  
Increased Sensitivity

ABSTRACTLeptospira interrogansis a global zoonotic pathogen and is the causative agent of leptospirosis, an endemic disease of humans and animals worldwide. There is limited understanding of leptospiral pathogenesis; therefore, further elucidation of the mechanisms involved would aid in vaccine development and the prevention of infection. HtpG (high-temperatureproteinG) is the bacterial homolog to the highly conserved molecular chaperone Hsp90 and is important in the stress responses of many bacteria. The specific role of HtpG, especially in bacterial pathogenesis, remains largely unknown. Through the use of anL. interroganshtpGtransposon insertion mutant, this study demonstrates thatL. interrogansHtpG is essential for virulence in the hamster model of acute leptospirosis. Complementation of thehtpGmutant completely restored virulence. Surprisingly, thehtpGmutant did not appear to show sensitivity to heat or oxidative stress, phenotypes common inhtpGmutants in other bacterial species. Furthermore, the mutant did not show increased sensitivity to serum complement, reduced survival within macrophages, or altered protein or lipopolysaccharide expression. The underlying cause for attenuation thus remains unknown, but HtpG is a novel leptospiral virulence factor and one of only a very small number identified to date.

scholarly journals CtBP impedes JNK- and Upd/STAT-driven cell fate misspecifications in regenerating Drosophila imaginal discs

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Melanie I Worley ◽  
Larissa A Alexander ◽  
Iswar K Hariharan
Keyword(s):  
Cell Fate ◽  
Tissue Damage ◽  
Binding Protein ◽  
Ectopic Expression ◽  
Cell Types ◽  
Imaginal Discs ◽  
Cell Fates ◽  
Genetic Ablation ◽  
Compartment Boundary ◽  
Wing Pouch

Regeneration following tissue damage often necessitates a mechanism for cellular re-programming, so that surviving cells can give rise to all cell types originally found in the damaged tissue. This process, if unchecked, can also generate cell types that are inappropriate for a given location. We conducted a screen for genes that negatively regulate the frequency of notum-to-wing transformations following genetic ablation and regeneration of the wing pouch, from which we identified mutations in the transcriptional co-repressor C-terminal Binding Protein (CtBP). When CtBP function is reduced, ablation of the pouch can activate the JNK/AP-1 and JAK/STAT pathways in the notum to destabilize cell fates. Ectopic expression of Wingless and Dilp8 precede the formation of the ectopic pouch, which is subsequently generated by recruitment of both anterior and posterior cells near the compartment boundary. Thus, CtBP stabilizes cell fates following damage by opposing the destabilizing effects of the JNK/AP-1 and JAK/STAT pathways.

scholarly journals Maintenance of Cell Fates by Regulation of the Histone Variant H3.3 in Caenorhabditis elegans

2018 ◽  
Author(s):  
Yukimasa Shibata ◽  
Kiyoji Nishiwaki
Keyword(s):  
Caenorhabditis Elegans ◽  
Cell Fate ◽  
Binding Protein ◽  
Ectopic Expression ◽  
Cell Types ◽  
Histone Variants ◽  
Histone Variant ◽  
Histone H4 ◽  
Cell Fates ◽  
Selector Genes

HighlightsTLK-1 maintains cell fates by repression of selector genesTLK-1 and downstream H3 chaperone CAF1 inhibit H3.3 depositionLoss of sin-3 suppresses the defect in cell-fate maintenance of tlk-1 mutantsAcH4-binding protein BET-1 is necessary for sin-3 suppressionSummaryCell-fate maintenance is important to preserve the variety of cell types that are essential for the formation and function of tissues. We previously showed that the acetylated histone H4-binding protein BET-1 maintains cell fate by recruiting the histone variant H2A.z. Here, we report that Caenorhabditis elegans tousled-like kinase TLK-1 and the histone H3 chaperone CAF1 maintain cell fate by preventing the incorporation of histone variant H3.3 into nucleosomes, thereby repressing ectopic expression of transcription factors that induce cell-fate specification. Genetic analyses suggested that TLK-1 and BET-1 act in parallel pathways. In tlk-1 mutants, the loss of SIN-3, which promotes histone acetylation, suppressed a defect in cell-fate maintenance in a manner dependent on MYST family histone acetyltransferase MYS-2 and BET-1. sin-3 mutation also suppressed abnormal H3.3 incorporation. Thus, we propose that the regulation and interaction of histone variants play crucial roles in cell-fate maintenance through the regulation of selector genes.

scholarly journals LIN-12/Notch signaling instructs postsynaptic muscle arm development by regulating UNC-40/DCC and MADD-2 in Caenorhabditis elegans

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Pengpeng Li ◽  
Kevin M Collins ◽  
Michael R Koelle ◽  
Kang Shen
Keyword(s):  
Nervous System ◽  
Caenorhabditis Elegans ◽  
Notch Signaling ◽  
Cell Fate ◽  
Dendritic Spine ◽  
Target Selection ◽  
Ectopic Expression ◽  
Cell Types ◽  
Synaptic Connectivity ◽  
Target Cells

The diverse cell types and the precise synaptic connectivity between them are the cardinal features of the nervous system. Little is known about how cell fate diversification is linked to synaptic target choices. Here we investigate how presynaptic neurons select one type of muscles, vm2, as a synaptic target and form synapses on its dendritic spine-like muscle arms. We found that the Notch-Delta pathway was required to distinguish target from non-target muscles. APX-1/Delta acts in surrounding cells including the non-target vm1 to activate LIN-12/Notch in the target vm2. LIN-12 functions cell-autonomously to up-regulate the expression of UNC-40/DCC and MADD-2 in vm2, which in turn function together to promote muscle arm formation and guidance. Ectopic expression of UNC-40/DCC in non-target vm1 muscle is sufficient to induce muscle arm extension from these cells. Therefore, the LIN-12/Notch signaling specifies target selection by selectively up-regulating guidance molecules and forming muscle arms in target cells.

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