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1561. UTX and UTY Demonstrate Histone Demethylase-Independent Function in Mouse Embryonic Development

Title Tesim:
UTX and UTY Demonstrate Histone Demethylase-Independent Function in Mouse Embryonic Development
Creator:
Yokoyama, Shigeyuki, Sengoku, Toru, Shpargel, Karl B., and Magnuson, Terry
Date of publication:
2012
Abstract Tesim:
UTX (KDM6A) and UTY are homologous X and Y chromosome members of the Histone H3 Lysine 27 (H3K27) demethylase gene family. UTX can demethylate H3K27; however, in vitro assays suggest that human UTY has lost enzymatic activity due to sequence divergence. We produced mouse mutations in both Utx and Uty. Homozygous Utx mutant female embryos are mid-gestational lethal with defects in neural tube, yolk sac, and cardiac development. We demonstrate that mouse UTY is devoid of in vivo demethylase activity, so hemizygous XUtx− Y+ mutant male embryos should phenocopy homozygous XUtx− XUtx− females. However, XUtx− Y+ mutant male embryos develop to term; although runted, approximately 25% survive postnatally reaching adulthood. Hemizygous X+ YUty− mutant males are viable. In contrast, compound hemizygous XUtx− YUty− males phenocopy homozygous XUtx− XUtx− females. Therefore, despite divergence of UTX and UTY in catalyzing H3K27 demethylation, they maintain functional redundancy during embryonic development. Our data suggest that UTX and UTY are able to regulate gene activity through demethylase independent mechanisms. We conclude that UTX H3K27 demethylation is non-essential for embryonic viability.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/e1hf-wp69
Identifier:
Publisher DOI: https://doi.org/10.1371/journal.pgen.1002964, PMCID: PMC3459986, Onescience id: b13dd5de36d7802faa1460b06b4c460da763e13d, and PMID: 23028370
ISSN:
1553-7404 and 1553-7390
Journal Issue:
9
Journal Title:
PLoS Genetics
Journal Volume:
8
Keyword:
Mice, Hemizygote, Animals, Homozygote, Histone Demethylases, Mutation, Female, Jumonji Domain-Containing Histone Demethylases, Gene Expression Regulation, Developmental, Methylation, Proteins, Male, Humans, Embryonic Development, and Minor Histocompatibility Antigens
Language Label:
English
Page Start:
e1002964
Person:
Yokoyama, Shigeyuki, Sengoku, Toru, Shpargel, Karl B., and Magnuson, Terry
Rights Statement Label:
In Copyright
Source:
qb98mp604

1562. Two-Component Elements Mediate Interactions between Cytokinin and Salicylic Acid in Plant Immunity

Title Tesim:
Two-Component Elements Mediate Interactions between Cytokinin and Salicylic Acid in Plant Immunity
Creator:
Hutchison, Claire E., Kieber, Joseph J., To, Jennifer P. C., Ferreira, Fernando J., Dangl, Jeffery L., Schaller, G. Eric, Epple, Petra, and Argueso, Cristiana T.
Date of publication:
2012
Abstract Tesim:
Recent studies have revealed an important role for hormones in plant immunity. We are now beginning to understand the contribution of crosstalk among different hormone signaling networks to the outcome of plant–pathogen interactions. Cytokinins are plant hormones that regulate development and responses to the environment. Cytokinin signaling involves a phosphorelay circuitry similar to two-component systems used by bacteria and fungi to perceive and react to various environmental stimuli. In this study, we asked whether cytokinin and components of cytokinin signaling contribute to plant immunity. We demonstrate that cytokinin levels in Arabidopsis are important in determining the amplitude of immune responses, ultimately influencing the outcome of plant–pathogen interactions. We show that high concentrations of cytokinin lead to increased defense responses to a virulent oomycete pathogen, through a process that is dependent on salicylic acid (SA) accumulation and activation of defense gene expression. Surprisingly, treatment with lower concentrations of cytokinin results in increased susceptibility. These functions for cytokinin in plant immunity require a host phosphorelay system and are mediated in part by type-A response regulators, which act as negative regulators of basal and pathogen-induced SA–dependent gene expression. Our results support a model in which cytokinin up-regulates plant immunity via an elevation of SA–dependent defense responses and in which SA in turn feedback-inhibits cytokinin signaling. The crosstalk between cytokinin and SA signaling networks may help plants fine-tune defense responses against pathogens.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/zycw-yb24
Identifier:
PMCID: PMC3266875, Onescience id: 6d81abf5527339b6262b1552ec533950f692c4dc, Publisher DOI: https://doi.org/10.1371/journal.pgen.1002448, and PMID: 22291601
ISSN:
1553-7404 and 1553-7390
Journal Issue:
1
Journal Title:
PLoS Genetics
Journal Volume:
8
Keyword:
Mutation, Plant Immunity, Histidine Kinase, Salicylic Acid, Plants, Genetically Modified, Gene Expression Regulation, Plant, Arabidopsis, Protein Kinases, Arabidopsis Proteins, Host-Pathogen Interactions, Cytokinins, Oomycetes, and Receptors, Cell Surface
Language Label:
English
Page Start:
e1002448
Person:
Hutchison, Claire E., Kieber, Joseph J., To, Jennifer P. C., Ferreira, Fernando J., Dangl, Jeffery L., Schaller, G. Eric, Epple, Petra, and Argueso, Cristiana T.
Rights Statement Label:
In Copyright
Source:
z603r5360

1563. The DNA Replication Factor RFC1 Is Required for Interference-Sensitive Meiotic Crossovers in Arabidopsis thaliana

Title Tesim:
The DNA Replication Factor RFC1 Is Required for Interference-Sensitive Meiotic Crossovers in Arabidopsis thaliana
Creator:
Ma, Hong, Shi, Qian, Gong, Zhizhong, Huang, Jiyue, Hong, Yue, Copenhaver, Gregory P., Wang, Yingxiang, and Cheng, Zhihao
Date of publication:
2012
Abstract Tesim:
During meiotic recombination, induced double-strand breaks (DSBs) are processed into crossovers (COs) and non-COs (NCO); the former are required for proper chromosome segregation and fertility. DNA synthesis is essential in current models of meiotic recombination pathways and includes only leading strand DNA synthesis, but few genes crucial for DNA synthesis have been tested genetically for their functions in meiosis. Furthermore, lagging strand synthesis has been assumed to be unnecessary. Here we show that the Arabidopsis thaliana DNA REPLICATION FACTOR C1 (RFC1) important for lagging strand synthesis is necessary for fertility, meiotic bivalent formation, and homolog segregation. Loss of meiotic RFC1 function caused abnormal meiotic chromosome association and other cytological defects; genetic analyses with other meiotic mutations indicate that RFC1 acts in the MSH4-dependent interference-sensitive pathway for CO formation. In a rfc1 mutant, residual pollen viability is MUS81-dependent and COs exhibit essentially no interference, indicating that these COs form via the MUS81-dependent interference-insensitive pathway. We hypothesize that lagging strand DNA synthesis is important for the formation of double Holliday junctions, but not alternative recombination intermediates. That RFC1 is found in divergent eukaryotes suggests a previously unrecognized and highly conserved role for DNA synthesis in discriminating between recombination pathways.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/yecy-0b49
Identifier:
Publisher DOI: https://doi.org/10.1371/journal.pgen.1003039, PMCID: PMC3493451, PMID: 23144629, and Onescience id: 3495903a1efc761cc2da57eddeaa5bdfb21d1f0e
ISSN:
1553-7404 and 1553-7390
Journal Issue:
11
Journal Title:
PLoS Genetics
Journal Volume:
8
Keyword:
Replication Protein C, Meiosis, Mutation, Chromosome Segregation, Homologous Recombination, Crossing Over, Genetic, DNA Helicases, Arabidopsis, DNA Replication, DNA Breaks, Double-Stranded, and Chromosomes, Plant
Language Label:
English
Page Start:
e1003039
Person:
Ma, Hong, Shi, Qian, Gong, Zhizhong, Huang, Jiyue, Hong, Yue, Copenhaver, Gregory P., Wang, Yingxiang, and Cheng, Zhihao
Rights Statement Label:
In Copyright
Source:
n009w923j

1564. The Burkholderia bcpAIOB Genes Define Unique Classes of Two-Partner Secretion and Contact Dependent Growth Inhibition Systems

Title Tesim:
The Burkholderia bcpAIOB Genes Define Unique Classes of Two-Partner Secretion and Contact Dependent Growth Inhibition Systems
Creator:
Anderson, Melissa S., Garcia, Erin C., and Cotter, Peggy A.
Date of publication:
2012
Abstract Tesim:
Microbes have evolved many strategies to adapt to changes in environmental conditions and population structures, including cooperation and competition. One apparently competitive mechanism is contact dependent growth inhibition (CDI). Identified in Escherichia coli, CDI is mediated by Two–Partner Secretion (TPS) pathway proteins, CdiA and CdiB. Upon cell contact, the toxic C-terminus of the TpsA family member CdiA, called the CdiA-CT, inhibits the growth of CDI− bacteria. CDI+ bacteria are protected from autoinhibition by an immunity protein, CdiI. Bioinformatic analyses indicate that CDI systems are widespread amongst α, β, and γ proteobacteria and that the CdiA-CTs and CdiI proteins are highly variable. CdiI proteins protect against CDI in an allele-specific manner. Here we identify predicted CDI system-encoding loci in species of Burkholderia, Ralstonia and Cupriavidus, named bcpAIOB, that are distinguished from previously-described CDI systems by gene order and the presence of a small ORF, bcpO, located 5′ to the gene encoding the TpsB family member. A requirement for bcpO in function of BcpA (the TpsA family member) was demonstrated, indicating that bcpAIOB define a novel class of TPS system. Using fluorescence microscopy and flow cytometry, we show that these genes are expressed in a probabilistic manner during culture of Burkholderia thailandensis in liquid medium. The bcpAIOB genes and extracellular DNA were required for autoaggregation and adherence to an abiotic surface, suggesting that CDI is required for biofilm formation, an activity not previously attributed to CDI. By contrast to what has been observed in E. coli, the B. thailandensis bcpAIOB genes only mediated interbacterial competition on a solid surface. Competition occurred in a defined spatiotemporal manner and was abrogated by allele-specific immunity. Our data indicate that the bcpAIOB genes encode distinct classes of CDI and TPS systems that appear to function in sociomicrobiological community development.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/d76t-qs87
Identifier:
PMID: 22912595, Onescience id: 3032cb83787f0bec48a50bf2324a9a3ff1a3f370, PMCID: PMC3415462, and Publisher DOI: https://doi.org/10.1371/journal.pgen.1002877
ISSN:
1553-7404 and 1553-7390
Journal Issue:
8
Journal Title:
PLoS Genetics
Journal Volume:
8
Keyword:
Membrane Proteins, CdiA protein, E coli, Escherichia coli Proteins, Antibiosis, CdiB protein, E coli, Species Specificity, Microscopy, Fluorescence, Protein Isoforms, Escherichia coli, Burkholderia, Flow Cytometry, and Biofilms
Language Label:
English
Page Start:
e1002877
Person:
Anderson, Melissa S., Garcia, Erin C., and Cotter, Peggy A.
Rights Statement Label:
In Copyright
Source:
gh93h626t

1565. Systems Genetic Analysis of Osteoblast-Lineage Cells

Title Tesim:
Systems Genetic Analysis of Osteoblast-Lineage Cells
Creator:
Bennett, Brian J., Lusis, Aldons J., Eskin, Eleazar, De Backer, Olivier, Calabrese, Gina, Orozco, Luz, Kang, Hyun M., Farber, Charles R., and Dombret, Carlos
Date of publication:
2012
Abstract Tesim:
The osteoblast-lineage consists of cells at various stages of maturation that are essential for skeletal development, growth, and maintenance. Over the past decade, many of the signaling cascades that regulate this lineage have been elucidated; however, little is known of the networks that coordinate, modulate, and transmit these signals. Here, we identify a gene network specific to the osteoblast-lineage through the reconstruction of a bone co-expression network using microarray profiles collected on 96 Hybrid Mouse Diversity Panel (HMDP) inbred strains. Of the 21 modules that comprised the bone network, module 9 (M9) contained genes that were highly correlated with prototypical osteoblast maker genes and were more highly expressed in osteoblasts relative to other bone cells. In addition, the M9 contained many of the key genes that define the osteoblast-lineage, which together suggested that it was specific to this lineage. To use the M9 to identify novel osteoblast genes and highlight its biological relevance, we knocked-down the expression of its two most connected “hub” genes, Maged1 and Pard6g. Their perturbation altered both osteoblast proliferation and differentiation. Furthermore, we demonstrated the mice deficient in Maged1 had decreased bone mineral density (BMD). It was also discovered that a local expression quantitative trait locus (eQTL) regulating the Wnt signaling antagonist Sfrp1 was a key driver of the M9. We also show that the M9 is associated with BMD in the HMDP and is enriched for genes implicated in the regulation of human BMD through genome-wide association studies. In conclusion, we have identified a physiologically relevant gene network and used it to discover novel genes and regulatory mechanisms involved in the function of osteoblast-lineage cells. Our results highlight the power of harnessing natural genetic variation to generate co-expression networks that can be used to gain insight into the function of specific cell-types.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/hszf-a265
Identifier:
PMCID: PMC3531492, Onescience id: 3590c5fe9a6f3b08923827aa41c25849c3935eb2, Publisher DOI: https://doi.org/10.1371/journal.pgen.1003150, and PMID: 23300464
ISSN:
1553-7390 and 1553-7404
Journal Issue:
12
Journal Title:
PLoS Genetics
Journal Volume:
8
Keyword:
Osteoblasts, Animals, Neoplasm Proteins, Genome-Wide Association Study, Oligonucleotide Array Sequence Analysis, Intercellular Signaling Peptides and Proteins, Cell Line, Quantitative Trait Loci, Mice, Cell Lineage, Gene Regulatory Networks, Membrane Proteins, Gene Expression Regulation, Developmental, Humans, and Bone Density
Language Label:
English
Page Start:
e1003150
Person:
Bennett, Brian J., Lusis, Aldons J., Eskin, Eleazar, De Backer, Olivier, Calabrese, Gina, Orozco, Luz, Kang, Hyun M., Farber, Charles R., and Dombret, Carlos
Rights Statement Label:
In Copyright
Source:
k3569c29x

1566. Stratifying Type 2 Diabetes Cases by BMI Identifies Genetic Risk Variants in LAMA1 and Enrichment for Risk Variants in Lean Compared to Obese Cases

Title Tesim:
Stratifying Type 2 Diabetes Cases by BMI Identifies Genetic Risk Variants in LAMA1 and Enrichment for Risk Variants in Lean Compared to Obese Cases
Creator:
Johnson, Andrew D., Ganser, Martha, Steinthorsdottir, Valgerdur, Green, Todd, Li, Man, Hadjadj, Samy, Balkau, Beverley, Bonnycastle, Lori, Collins, Francis S., Burtt, Noël P., Bergman, Richard N., Grallert, Harald, Kottgen, Anna, Navarro, Pau, Campbell, Harry, Arking, Dan E., Benediktsson, Rafn, Perry, John R. B., Voight, Benjamin F., Scott, Robert A., Boerwinkle, Eric, Dupuis, Josée, Almgren, Peter, Aulchenko, Yurii, Hattersley, Andrew T., Amin, Najaf, Hofman, Albert, Charpentier, Guillaume, Qi, Lu, Gieger, Christian, Herder, Christian, and Yengo, Loïc
Date of publication:
2012
Abstract Tesim:
Common diseases such as type 2 diabetes are phenotypically heterogeneous. Obesity is a major risk factor for type 2 diabetes, but patients vary appreciably in body mass index. We hypothesized that the genetic predisposition to the disease may be different in lean (BMI<25 Kg/m2) compared to obese cases (BMI≥30 Kg/m2). We performed two case-control genome-wide studies using two accepted cut-offs for defining individuals as overweight or obese. We used 2,112 lean type 2 diabetes cases (BMI<25 kg/m2) or 4,123 obese cases (BMI≥30 kg/m2), and 54,412 un-stratified controls. Replication was performed in 2,881 lean cases or 8,702 obese cases, and 18,957 un-stratified controls. To assess the effects of known signals, we tested the individual and combined effects of SNPs representing 36 type 2 diabetes loci. After combining data from discovery and replication datasets, we identified two signals not previously reported in Europeans. A variant (rs8090011) in the LAMA1 gene was associated with type 2 diabetes in lean cases (P = 8.4×10−9, OR = 1.13 [95% CI 1.09–1.18]), and this association was stronger than that in obese cases (P = 0.04, OR = 1.03 [95% CI 1.00–1.06]). A variant in HMG20A—previously identified in South Asians but not Europeans—was associated with type 2 diabetes in obese cases (P = 1.3×10−8, OR = 1.11 [95% CI 1.07–1.15]), although this association was not significantly stronger than that in lean cases (P = 0.02, OR = 1.09 [95% CI 1.02–1.17]). For 36 known type 2 diabetes loci, 29 had a larger odds ratio in the lean compared to obese (binomial P = 0.0002). In the lean analysis, we observed a weighted per-risk allele OR = 1.13 [95% CI 1.10–1.17], P = 3.2×10−14. This was larger than the same model fitted in the obese analysis where the OR = 1.06 [95% CI 1.05–1.08], P = 2.2×10−16. This study provides evidence that stratification of type 2 diabetes cases by BMI may help identify additional risk variants and that lean cases may have a stronger genetic predisposition to type 2 diabetes.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/9k4n-rx53
Identifier:
PMCID: PMC3364960, PMID: 22693455, Publisher DOI: https://doi.org/10.1371/journal.pgen.1002741, and Onescience id: facac66126e95ababfa79f611c47b9ed30cf47ce
ISSN:
1553-7404 and 1553-7390
Journal Issue:
5
Journal Title:
PLoS Genetics
Journal Volume:
8
Keyword:
Female, Alleles, Diabetes Mellitus, Genetics & Heredity, GENOME-WIDE ASSOCIATION, GLUCOSE, Aged, Body Mass Index, Science & Technology, Genetic Predisposition to Disease, Case-Control Studies, CELLS, GENETICS & HEREDITY, Type 2, Genome-Wide Association Study, EXPRESSION, Life Sciences & Biomedicine, DIFFERENTIATION, DISEASE, SUSCEPTIBILITY LOCI, MOUSE, European Continental Ancestry Group, Asian Continental Ancestry Group, INSULIN, and PROTEIN
Language Label:
English
Page Start:
e1002741
Person:
Johnson, Andrew D., Ganser, Martha, Steinthorsdottir, Valgerdur, Green, Todd, Li, Man, Hadjadj, Samy, Balkau, Beverley, Bonnycastle, Lori, Collins, Francis S., Burtt, Noël P., Bergman, Richard N., Grallert, Harald, Kottgen, Anna, Navarro, Pau, Campbell, Harry, Arking, Dan E., Benediktsson, Rafn, Perry, John R. B., Voight, Benjamin F., Scott, Robert A., Boerwinkle, Eric, Dupuis, Josée, Almgren, Peter, Aulchenko, Yurii, Hattersley, Andrew T., Amin, Najaf, Hofman, Albert, Charpentier, Guillaume, Qi, Lu, Gieger, Christian, Herder, Christian, and Yengo, Loïc
Rights Statement Label:
In Copyright
Source:
t722hh89w

1567. Specific Missense Alleles of the Arabidopsis Jasmonic Acid Co-Receptor COI1 Regulate Innate Immune Receptor Accumulation and Function

Title Tesim:
Specific Missense Alleles of the Arabidopsis Jasmonic Acid Co-Receptor COI1 Regulate Innate Immune Receptor Accumulation and Function
Creator:
Chung, Eui-Hwan, He, Yijian, Hubert, David A., Tornero, Pablo, and Dangl, Jeffery L.
Date of publication:
2012
Abstract Tesim:
Plants utilize proteins containing nucleotide binding site (NB) and leucine-rich repeat (LRR) domains as intracellular innate immune receptors to recognize pathogens and initiate defense responses. Since mis-activation of defense responses can lead to tissue damage and even developmental arrest, proper regulation of NB–LRR protein signaling is critical. RAR1, SGT1, and HSP90 act as regulatory chaperones of pre-activation NB–LRR steady-state proteins. We extended our analysis of mutants derived from a rar1 suppressor screen and present two allelic rar1 suppressor (rsp) mutations of Arabidopsis COI1. Like all other coi1 mutations, coi1rsp missense mutations impair Jasmonic Acid (JA) signaling resulting in JA–insensitivity. However, unlike previously identified coi1 alleles, both coi1rsp alleles lack a male sterile phenotype. The coi1rsp mutants express two sets of disease resistance phenotypes. The first, also observed in coi1-1 null allele, includes enhanced basal defense against the virulent bacterial pathogen Pto DC3000 and enhanced effector-triggered immunity (ETI) mediated by the NB–LRR RPM1 protein in both rar1 and wild-type backgrounds. These enhanced disease resistance phenotypes depend on the JA signaling function of COI1. Additionally, the coi1rsp mutants showed a unique inability to properly regulate RPM1 accumulation and HR, exhibited increased RPM1 levels in rar1, and weakened RPM1-mediated HR in RAR1. Importantly, there was no change in the steady-state levels or HR function of RPM1 in coi1-1. These results suggest that the coi1rsp proteins regulate NB–LRR protein accumulation independent of JA signaling. Based on the phenotypic similarities and genetic interactions among coi1rsp, sgt1b, and hsp90.2rsp mutants, our data suggest that COI1 affects NB–LRR accumulation via two NB–LRR co-chaperones, SGT1b and HSP90. Together, our data demonstrate a role for COI1 in disease resistance independent of JA signaling and provide a molecular link between the JA and NB–LRR signaling pathways.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/zans-0486
Identifier:
Onescience id: 22e63616b19e367a4394cf38f3d442c66d59f552, PMCID: PMC3475666, Publisher DOI: https://doi.org/10.1371/journal.pgen.1003018, and PMID: 23093946
ISSN:
1553-7390 and 1553-7404
Journal Issue:
10
Journal Title:
PLoS Genetics
Journal Volume:
8
Keyword:
changement, résistance, science, Artículo, Territoire fédéral de Canberra (Australie), Ubiquitin-Ligase, génétique, Cop9 signalosome, Jaz proteins, Nucleotide-Binding site, Downy mildew resistance, Disease resistance protein, Defense responses, Pathogen defense, génétique antique, Signaling pathways, III effectors, and plomb
Language Label:
English
Page Start:
e1003018
Person:
Chung, Eui-Hwan, He, Yijian, Hubert, David A., Tornero, Pablo, and Dangl, Jeffery L.
Rights Statement Label:
In Copyright
Source:
9306t696j

1568. S Phase–Coupled E2f1 Destruction Ensures Homeostasis in Proliferating Tissues

Title Tesim:
S Phase–Coupled E2f1 Destruction Ensures Homeostasis in Proliferating Tissues
Creator:
Duronio, Robert J. and Davidson, Jean M.
Date of publication:
2012
Abstract Tesim:
Precise control of cell cycle regulators is critical for normal development and tissue homeostasis. E2F transcription factors are activated during G1 to drive the G1-S transition and are then inhibited during S phase by a variety of mechanisms. Here, we genetically manipulate the single Drosophila activator E2F (E2f1) to explore the developmental requirement for S phase–coupled E2F down-regulation. Expression of an E2f1 mutant that is not destroyed during S phase drives cell cycle progression and causes apoptosis. Interestingly, this apoptosis is not exclusively the result of inappropriate cell cycle progression, because a stable E2f1 mutant that cannot function as a transcription factor or drive cell cycle progression also triggers apoptosis. This observation suggests that the inappropriate presence of E2f1 protein during S phase can trigger apoptosis by mechanisms that are independent of E2F acting directly at target genes. The ability of S phase-stabilized E2f1 to trigger apoptosis requires an interaction between E2f1 and the Drosophila pRb homolog, Rbf1, and involves induction of the pro-apoptotic gene, hid. Simultaneously blocking E2f1 destruction during S phase and inhibiting the induction of apoptosis results in tissue overgrowth and lethality. We propose that inappropriate accumulation of E2f1 protein during S phase triggers the elimination of potentially hyperplastic cells via apoptosis in order to ensure normal development of rapidly proliferating tissues.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/d3ff-4v74
Identifier:
Onescience id: 6db5dd4a50734ff26940773b82847408c50589f4, PMID: 22916021, Publisher DOI: https://doi.org/10.1371/journal.pgen.1002831, and PMCID: PMC3420931
ISSN:
1553-7404 and 1553-7390
Journal Issue:
8
Journal Title:
PLoS Genetics
Journal Volume:
8
Keyword:
Gene Expression Regulation, Developmental, Drosophila Proteins, DNA, Cell Proliferation, Neuropeptides, G1 Phase, Animals, Proteolysis, E2F1 Transcription Factor, Mutation, Drosophila melanogaster, Homeostasis, Apoptosis, and Larva
Language Label:
English
Page Start:
e1002831
Person:
Duronio, Robert J. and Davidson, Jean M.
Rights Statement Label:
In Copyright
Source:
1544bx50v

1569. Runs of Homozygosity Implicate Autozygosity as a Schizophrenia Risk Factor

Title Tesim:
Runs of Homozygosity Implicate Autozygosity as a Schizophrenia Risk Factor
Creator:
Ripke, Stephan, Sullivan, Patrick F., Lee, Sang Hong, Keller, Matthew C., Howrigan, Daniel P., Simonson, Matthew A., Gejman, Pablo V., Levinson, Douglas F., Neale, Ben M., and Lencz, Todd
Date of publication:
2012
Abstract Tesim:
Autozygosity occurs when two chromosomal segments that are identical from a common ancestor are inherited from each parent. This occurs at high rates in the offspring of mates who are closely related (inbreeding), but also occurs at lower levels among the offspring of distantly related mates. Here, we use runs of homozygosity in genome-wide SNP data to estimate the proportion of the autosome that exists in autozygous tracts in 9,388 cases with schizophrenia and 12,456 controls. We estimate that the odds of schizophrenia increase by ∼17% for every 1% increase in genome-wide autozygosity. This association is not due to one or a few regions, but results from many autozygous segments spread throughout the genome, and is consistent with a role for multiple recessive or partially recessive alleles in the etiology of schizophrenia. Such a bias towards recessivity suggests that alleles that increase the risk of schizophrenia have been selected against over evolutionary time.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/emw9-4b41
Identifier:
PMCID: PMC3325203, Publisher DOI: https://doi.org/10.1371/journal.pgen.1002656, Onescience id: dab71321621e9da4f1b649d74cb59c0761506da7, and PMID: 22511889
ISSN:
1553-7390 and 1553-7404
Journal Issue:
4
Journal Title:
PLoS Genetics
Journal Volume:
8
Keyword:
genetics, Journal Article, evolutionary biology, genome-wide association studies, psychoses, mental health, psychiatry, schizophrenia, population genetics, biology, medicine, haplotypes, evolutionary genetics, and human genetics
Language Label:
English
Page Start:
e1002656
Person:
Ripke, Stephan, Sullivan, Patrick F., Lee, Sang Hong, Keller, Matthew C., Howrigan, Daniel P., Simonson, Matthew A., Gejman, Pablo V., Levinson, Douglas F., Neale, Ben M., and Lencz, Todd
Rights Statement Label:
In Copyright
Source:
41687r53q

1570. Polyglutamine Toxicity Is Controlled by Prion Composition and Gene Dosage in Yeast

Title Tesim:
Polyglutamine Toxicity Is Controlled by Prion Composition and Gene Dosage in Yeast
Creator:
Gong, He, Gokhale, Kavita, Mieczkowski, Piotr, Sherman, Michael Y., Chandramowlishwaran, Pavithra, Newnam, Gary P., Chernoff, Yury O., Allen, Kim D., and Romanova, Nina V.
Date of publication:
2012
Abstract Tesim:
Polyglutamine expansion causes diseases in humans and other mammals. One example is Huntington's disease. Fragments of human huntingtin protein having an expanded polyglutamine stretch form aggregates and cause cytotoxicity in yeast cells bearing endogenous QN-rich proteins in the aggregated (prion) form. Attachment of the proline(P)-rich region targets polyglutamines to the large perinuclear deposit (aggresome). Aggresome formation ameliorates polyglutamine cytotoxicity in cells containing only the prion form of Rnq1 protein. Here we show that expanded polyglutamines both with (poly-QP) or without (poly-Q) a P-rich stretch remain toxic in the presence of the prion form of translation termination (release) factor Sup35 (eRF3). A Sup35 derivative that lacks the QN-rich domain and is unable to be incorporated into aggregates counteracts cytotoxicity, suggesting that toxicity is due to Sup35 sequestration. Increase in the levels of another release factor, Sup45 (eRF1), due to either disomy by chromosome II containing the SUP45 gene or to introduction of the SUP45-bearing plasmid counteracts poly-Q or poly-QP toxicity in the presence of the Sup35 prion. Protein analysis confirms that polyglutamines alter aggregation patterns of Sup35 and promote aggregation of Sup45, while excess Sup45 counteracts these effects. Our data show that one and the same mode of polyglutamine aggregation could be cytoprotective or cytotoxic, depending on the composition of other aggregates in a eukaryotic cell, and demonstrate that other aggregates expand the range of proteins that are susceptible to sequestration by polyglutamines.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/9r1s-2673
Identifier:
PMCID: PMC3334884, Onescience id: 781c64446718f0002e696a555cb3d8e97f65f65e, Publisher DOI: https://doi.org/10.1371/journal.pgen.1002634, and PMID: 22536159
ISSN:
1553-7404 and 1553-7390
Journal Issue:
4
Journal Title:
PLoS Genetics
Journal Volume:
8
Keyword:
Epigenesis, Genetic, Sequence Deletion, Protein Biosynthesis, HTT protein, human, Gene Dosage, Nerve Tissue Proteins, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Protein Binding, Prions, Humans, Peptides, Huntingtin Protein, and Peptide Termination Factors
Language Label:
English
Page Start:
e1002634
Person:
Gong, He, Gokhale, Kavita, Mieczkowski, Piotr, Sherman, Michael Y., Chandramowlishwaran, Pavithra, Newnam, Gary P., Chernoff, Yury O., Allen, Kim D., and Romanova, Nina V.
Rights Statement Label:
In Copyright
Source:
qn59qc28c