Histone Chaperone Paralogs Have Redundant, Co-operative and Divergent Functions in Yeast.
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ABSTRACT:
ORGANISM(S): Saccharomyces cerevisiae
PROVIDER: GSE134075 | GEO | 2019/07/11
REPOSITORIES: GEO
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Project description:Histone Chaperone Paralogs Have Redundant, Co-operative and Divergent Functions in Yeast.
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Project description:Gene duplications increase organismal robustness by providing freedom for gene divergence or by increasing gene dosage. The yeast histone chaperones Fpr3 and Fpr4 are paralogs that can assemble nucleosomes in vitro; however, the genomic locations they target and their functional relationship is poorly understood. We refined the yeast synthetic genetic array approach to enable the functional dissection of gene paralogs. Applying this method to Fpr3 and Fpr4 uncovered redundant, cooperative, and divergent functions. While Fpr3 is uniquely involved in chromosome segregation, Fpr3 and Fpr4 cooperate to regulate genes involved in polyphosphate metabolism and ribosome biogenesis. We find that the TRAMP5 RNA exosome is critical for fitness in ?fpr3?fpr4 yeast and leverage this information to identify an important role for Fpr4 at the 5' ends of protein coding genes. Additionally, Fpr4 and TRAMP5 negatively regulate RNAs from the nontranscribed spacers of ribosomal DNA. Yeast lacking Fpr3 and Fpr4 exhibit a genome instability phenotype at the ribosomal DNA, which implies that these histone chaperones regulate chromatin structure and DNA access at this location. Taken together. we provide genetic and transcriptomic evidence that Fpr3 and Fpr4 operate separately, cooperatively, and redundantly to regulate a variety of chromatin environments.
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Project description:Functional divergence of duplicate genes, or paralogs, is an important driver of novelty in evolution. In the model yeast Saccharomyces cerevisiae, there are 547 paralog gene pairs that survive from an interspecies Whole Genome Hybridization (WGH) that occurred ~100MYA. In this work, we report that ~1/6th (110) of these WGH paralogs pairs (or ohnologs) are differentially expressed with a striking pattern upon Protein Kinase A (PKA) inhibition. One member of each pair in this group has low basal expression that increases upon PKA inhibition, while the other has moderate and unchanging expression. For these genes, expression of orthologs upon PKA inhibition in the non-WGH species Kluyveromyces lactis and for PKA-related stresses in other budding yeasts shows unchanging expression, suggesting that lack of responsiveness to PKA was likely the typical ancestral phenotype prior to duplication. Promoter sequence analysis across related budding yeast species further revealed that the subsequent emergence of PKA-dependence took different evolutionary routes. In some examples, regulation by PKA and differential expression appears to have arisen following the WGH, while in others, regulation by PKA appears to have arisen in one of the two parental lineages prior to the WGH. More broadly, our results illustrate the unique opportunities presented by a WGH event for generating functional divergence by bringing together two parental lineages with separately evolved regulation into one species. We propose that functional divergence of two ohnologs can be facilitated through such regulatory divergence.
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Project description:Secreted immune proteases "Required for Cladosporium resistance-3" (Rcr3) and "Phytophthora-inhibited protease-1" (Pip1) of tomato (Solanum lycopersicum) are both inhibited by Avirulence-2 (Avr2) from the fungal plant pathogen Cladosporium fulvum. However, only Rcr3 acts as a decoy co-receptor that detects Avr2 in the presence of the Cf-2 immune receptor. Here, we identified crucial residues in tomato Rcr3 that are required for Cf-2-mediated signaling and bioengineered various proteases to trigger Avr2/Cf-2-dependent immunity. Despite substantial divergence in Rcr3 orthologs from eggplant (Solanum melongena) and tobacco (Nicotiana spp.), minimal alterations were sufficient to trigger Avr2/Cf-2-mediated immune signaling. By contrast, tomato Pip1 was bioengineered with 16 Rcr3-specific residues to initiate Avr2/Cf-2-triggered immune signaling. These residues cluster on one side of the protein next to the substrate-binding groove, indicating a potential Cf-2 interaction site. Our findings also revealed that Rcr3 and Pip1 have distinct substrate preferences determined by two variant residues and that both are suboptimal for binding Avr2. This study advances our understanding of Avr2 perception and opens avenues to bioengineer proteases to broaden pathogen recognition in other crops.
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Project description:Quorum sensing (QS) is a mechanism of synthesis and detection of signaling molecules to regulate gene expression and coordinate behaviors in bacterial populations. In Bacillus subtilis, multiple paralog Rap-Phr QS systems (receptor-signaling peptides) are highly redundant and multifunctional, interconnecting the regulation of differentiation processes such as sporulation and competence. However, their functions in the Bacillus cereus group are largely unknown. We evaluated the functions of Rap proteins in Bacillus thuringiensis Bt8741, which codes for eight Rap-Phr systems; these were individually overexpressed to study their participation in sporulation, biofilm formation, spreading, and extracellular proteolytic activity. Our results show that four Rap-Phr systems (RapC, RapK, RapF, and RapLike) inhibit sporulation, two of which (RapK and RapF) probably dephosphorylate Spo0F from the Spo0A phosphorelay; these two Rap proteins also inhibit biofilm formation. Four systems (RapC, RacF1, RacF2, and RapLike) participate in spreading inhibition; finally, six systems (RapC, -F, -F2, -I, and -I1 and RapLike) decrease extracellular proteolytic activity. We foresee that functions performed by Rap proteins of Bt8741 could also be carried out by Rap homologs in other strains within the B. cereus group. These results indicate that Rap-Phr systems constitute a highly multifunctional and redundant regulatory repertoire that enables B. thuringiensis and other species from the B. cereus group to efficiently regulate collective functions during their life cycle in the face of changing environments.IMPORTANCE The Bacillus cereus group of bacteria includes species of high economic, clinical, biological warfare, and biotechnological interest, e.g., B. anthracis in bioterrorism, B. cereus in food intoxications, and B. thuringiensis in biocontrol. Knowledge about the ecology of these bacteria is hindered by our limited understanding of the regulatory circuits that control differentiation and specialization processes. Here, we uncover the participation of eight Rap quorum-sensing receptors in collective functions of B. thuringiensis These proteins are highly multifunctional and redundant in their functions, linking ecologically relevant processes such as sporulation, biofilm formation, spreading, extracellular proteolytic activity, and probably other functions in species from the B. cereus group.
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Project description:Recent single-cell studies have revealed that yeast stress response involves multiple transcription factors that are temporally activated in pulses. However, it remains largely unclear whether and how these dynamic transcription factors temporally interact to regulate stress survival. Here we show that budding yeast cells can exploit the temporal relationship between paralogous general stress regulators, Msn2 and Msn4, during stress response. We found that individual pulses of Msn2 and Msn4 are largely redundant, and cells can enhance the expression of their shared target genes by increasing their temporal divergence. Thus, functional redundancy between these two paralogs is modulated in a dynamic manner to confer fitness advantages for yeast cells, which might feed back to promote the preservation of their functional redundancy. This evolutionary implication was supported by evidence from Msn2/Msn4 orthologs and analyses of other transcription factor paralogs. Together, we show a cell fate control mechanism through temporal redundancy modulation in yeast, which may represent an evolutionarily important strategy for maintaining functional redundancy between gene duplicates.
2021-03-06 | GSE161373 | GEO
Project description:Mendelian disorders are often caused by mutations in genes that are not lethal but induce functional distortions leading to diseases. Here we study the extent of gene duplicates that might compensate genes causing monogenic diseases. We provide evidence for pervasive functional redundancy of human monogenic disease genes (MDs) by duplicates by manifesting 1) genes involved in human genetic disorders are enriched in duplicates and 2) duplicated disease genes tend to have higher functional similarities with their closest paralogs in contrast to duplicated non-disease genes of similar age. We propose that functional compensation by duplication of genes masks the phenotypic effects of deleterious mutations and reduces the probability of purging the defective genes from the human population; this functional compensation could be further enhanced by higher purification selection between disease genes and their duplicates as well as their orthologous counterpart compared to non-disease genes. However, due to the intrinsic expression stochasticity among individuals, the deleterious mutations could still be present as genetic diseases in some subpopulations where the duplicate copies are expressed at low abundances. Consequently the defective genes are linked to genetic disorders while they continue propagating within the population. Our results provide insight into the molecular basis underlying the spreading of duplicated disease genes.
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Project description:The mammalian epidermis undergoes constant renewal replenished by a pool of stem cells and terminal differentiation of their progeny. This is accompanied by changes in gene expression and morphology orchestrated, in part, by epigenetic modifiers. Here, we defined the role of histone acetyltransferase KAT2A in epidermal homeostasis and provided a comparative analysis that revealed key functional divergence with its paralogue, KAT2B. In contrast to KAT2B's reported function in epidermal differentiation, KAT2A supports the undifferentiated state in keratinocytes. RNA-seq analysis of KAT2A- and KAT2B- depleted keratinocytes revealed dysregulated epidermal differentiation. Depletion of KAT2A led to premature expression of epidermal differentiation genes in the absence of inductive signals, whilst loss of KAT2B delayed differentiation. KAT2A acetyltransferase activity was indispensable in regulating epidermal differentiation gene expression. The metazoan-specific N-terminus of KAT2A was also required to support its function in keratinocytes. We further showed that the interplay between KAT2A- and KAT2B- mediated regulation was important for normal cutaneous wound healing in vivo. Overall, these findings reveal a distinct mechanism in which keratinocytes utilize a pair of highly homologous histone acetyltransferases to support divergent functions in self-renewal and differentiation processes.
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Project description:ChIP-chip assays to measure the occupancy of histone H3 K36me3 over the yeast genome in wildtype, isw1 and chd1 yeast strains. ChIPs were done with K36me3 antibody (Ab 9050) in G1 arrested yeast cells.
2012-07-25 | GSE32044 | GEO