Fralin Life Sciences Institute

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Abstracts from the 3rd Conference on Aneuploidy and Cancer: Clinical and Experimental Aspects
Cornish-Bowden, Athel; Rasnick, David; Heng, Henry H.; Horne, Steven; Abdallah, Batoul; Liu, Guo; Ye, Christine J.; Bloomfield, Mathew; Vincent, Mark D.; Aldaz, C. M.; Karlsson, Jenny; Valind, Anders; Jansson, Caroline; Gisselsson, David; Graves, Jennifer A. M.; Stepanenko, Aleksei A.; Andreieva, Svitlana V.; Korets, Kateryna V.; Mykytenko, Dmytro O.; Huleyuk, Nataliya L.; Baklaushev, Vladimir P.; Kovaleva, Oksana A.; Chekhonin, Vladimir P.; Vassetzky, Yegor S.; Avdieiev, Stanislav S.; Bakker, Bjorn; Taudt, Aaron S.; Belderbos, Mirjam E.; Porubsky, David; Spierings, Diana C. J.; de Jong, Tristan V.; Halsema, Nancy; Kazemier, Hinke G.; Hoekstra-Wakker, Karina; Bradley, Allan; de Bont, Eveline S. J. M.; van den Berg, Anke; Guryev, Victor; Lansdorp, Peter M.; Tatché, Maria C.; Foijer, Floris; Liehr, Thomas; Baudoin, Nicolaas C.; Nicholson, Joshua M.; Soto, Kimberly; Quintanilla, Isabel; Camps, Jordi; Cimini, Daniela; Dürrbaum, M.; Donnelly, N.; Passerini, V.; Kruse, C.; Habermann, B.; Storchová, Z.; Mandrioli, Daniele; Belpoggi, Fiorella; Silbergeld, Ellen K.; Perry, Melissa J.; Skotheim, Rolf I.; Løvf, Marthe; Johannessen, Bjarne; Hoff, Andreas M.; Zhao, Sen; SveeStrømme, Jonas M.; Sveen, Anita; Lothe, Ragnhild A.; Hehlmann, R.; Voskanyan, A.; Fabarius, A.; Böcking, Alfred; Biesterfeld, Stefan; Berynskyy, Leonid; Börgermann, Christof; Engers, Rainer; Dietz, Josef; Fritz, A.; Sehgal, N.; Vecerova, J.; Stojkovicz, B.; Ding, H.; Page, N.; Tye, C.; Bhattacharya, S.; Xu, J.; Stein, G.; Stein, J.; Berezney, R.; Gong, Xue; Grasedieck, Sarah; Swoboda, Julian; Rücker, Frank G.; Bullinger, Lars; Pollack, Jonathan R.; Roumelioti, Fani-Marlen; Chiourea, Maria; Raftopoulou, Christina; Gagos, Sarantis; Duesberg, Peter; Bloomfield, Mathew; Hwang, Sunyoung; Gustafsson, Hans T.; O’Sullivan, Ciara; Acevedo-Colina, Aracelli; Huang, Xinhe; Klose, Christian; Schevchenko, Andrej; Dickson, Robert C.; Cavaliere, Paola; Dephoure, Noah; Torres, Eduardo M.; Stampfer, Martha R.; Vrba, Lukas; LaBarge, Mark A.; Futscher, Bernard; Garbe, James C.; Trinh, Andrew L.; Zhou, Yi-Hong; Digman, Michelle (2017-06-22)
Accurate human microsatellite genotypes from high-throughput resequencing data using informed error profiles
Highnam, Gareth; Franck, Christopher T.; Martin, Andy; Stephens, Calvin; Puthige, Ashwin; Mittelman, David (Oxford University Press, 2013-01)
Repetitive sequences are biologically and clinically important because they can influence traits and disease, but repeats are challenging to analyse using short-read sequencing technology. We present a tool for genotyping microsatellite repeats called RepeatSeq, which uses Bayesian model selection guided by an empirically derived error model that incorporates sequence and read properties. Next, we apply RepeatSeq to high-coverage genomes from the 1000 Genomes Project to evaluate performance and accuracy. The software uses common formats, such as VCF, for compatibility with existing genome analysis pipelines. Source code and binaries are available at http://github.com/adaptivegenome/repeatseq.
Analysis of global gene expression changes in human bronchial epithelial cells exposed to spores of the allergenic fungus, Alternaria alternata
Babiceanu, Mihaela; Howard, B. A.; Rumore, A. C.; Kita, H.; Lawrence, Christopher B. (Frontiers, 2013-07-19)
Exposure and sensitivity to ubiquitous airborne fungi such as Alternaria alternata have long been implicated in the development, onset, and exacerbation of chronic allergic airway disorders. This present study is the first to investigate global changes in host gene expression during the interaction of cultured human bronchial epithelial cells and live Alternaria spores. In in vitro experiments human bronchial epithelial cells (BEAS-2B) were exposed to spores or media alone for 24 h. RNA was collected from three biological replicates per treatment and was used to assess changes in gene expression patterns using Affymetrix Human Genome U133 Plus 2.0 Arrays. In cells treated with Alternaria spores compared to controls, 613 probe sets representing 460 individual genes were found differentially expressed (p <= 0.05). In this set of 460 statistically significant, differentially expressed genes, 397 genes were found to be up-regulated and 63 were down-regulated. Of these 397 up-regulated genes, 156 genes were found to be up-regulated >= 2 fold. Interestingly, none of the 63 down-regulated genes were found differentially expressed at <=-2 fold. Differentially expressed genes were identified following statistical analysis and subsequently used for pathway and network evaluation. Interestingly, many cytokine and chemokine immune response genes were up-regulated with a particular emphasis on interferon-inducible genes. Genes involved in cell death, retinoic acid signaling, and TLR3 response pathways were also significantly up-regulated. Many of the differentially up-regulated genes have been shown in other systems to be associated with innate immunity, inflammation and/or allergic airway diseases. This study now provides substantial information for further investigating specific genes and innate immune system pathways activated by Alternaria in the context of allergic airway diseases.
A Burkholderia pseudomallei Colony Variant Necessary for Gastric Colonization
Austin, C. R.; Goodyear, A. W.; Bartek, I. L.; Stewart, A.; Sutherland, M. D.; Silva, E. B.; Zweifel, A.; Vitko, N. P.; Tuanyok, A.; Highnam, G.; Mittelman, D.; Keim, P.; Schweizer, H. P.; Vazquez-Torres, A.; Dow, S. W. C.; Voskuil, M. I. (American Society for Microbiology, 2015-01)
Diverse colony morphologies are a hallmark of Burkholderia pseudomallei recovered from infected patients. We observed that stresses that inhibit aerobic respiration shifted populations of B. pseudomallei from the canonical white colony morphotype toward two distinct, reversible, yet relatively stable yellow colony variants (YA and YB). As accumulating evidence supports the importance of B. pseudomallei enteric infection and gastric colonization, we tested the response of yellow variants to hypoxia, acidity, and stomach colonization. Yellow variants exhibited a competitive advantage under hypoxic and acidic conditions and alkalized culture media. The YB variant, although highly attenuated in acute virulence, was the only form capable of colonization and persistence in the murine stomach. The accumulation of extracellular DNA (eDNA) was a characteristic of YB as observed by 4',6-diamidino-2-phenylindole (DAPI) staining of gastric tissues, as well as in an in vitro stomach model where large amounts of eDNA were produced without cell lysis. Transposon mutagenesis identified a transcriptional regulator (BPSL1887, designated YelR) that when overexpressed produced the yellow phenotype. Deletion of yelR blocked a shift from white to the yellow forms. These data demonstrate that YB is a unique B. pseudomallei pathovariant controlled by YelR that is specifically adapted to the harsh gastric environment and necessary for persistent stomach colonization. IMPORTANCE Seemingly uniform populations of bacteria often contain subpopulations that are genetically identical but display unique characteristics which offer advantages when the population is faced with infrequent but predictable stresses. The pathogen Burkholderia pseudomallei is capable of forming several reversible colony types, and it interconverted between one white type and two yellow types under certain environmental stresses. The two yellow forms exhibited distinct advantages in low-oxygen and acidic environments. One yellow colony variant was the only form capable of chronic stomach colonization. Areas of gastric infection were marked by bacteria encased in a DNA matrix, and the yellow forms were able to produce large amounts of extracellular DNA in vitro. We also identified the regulator in control of yellow colony variant formation. These findings demonstrate a role in infection for colony variation and provide a mechanism for chronic stomach colonization-a frequently overlooked niche in melioidosis.
Cell Cycle Model System for Advancing Cancer Biomarker Research
Lazar, Iuliana M.; Hoeschele, Ina; de Morais, Juliana; Tenga, Milagros J. (Springer Nature, 2017-12-21)
Progress in understanding the complexity of a devastating disease such as cancer has underscored the need for developing comprehensive panels of molecular markers for early disease detection and precision medicine applications. The present study was conducted to assess whether a cohesive biological context can be assigned to protein markers derived from public data mining, and whether mass spectrometry can be utilized to screen for the co-expression of functionally related biomarkers to be recommended for further exploration in clinical context. Cell cycle arrest/release experiments of MCF7/SKBR3 breast cancer and MCF10 non-tumorigenic cells were used as a surrogate to support the production of proteins relevant to aberrant cell proliferation. Information downloaded from the scientific public domain was queried with bioinformatics tools to generate an initial list of 1038 cancer-associated proteins. Mass spectrometric analysis of cell extracts identified 352 proteins that could be matched to the public list. Differential expression, enrichment, and protein-protein interaction analysis of the proteomic data revealed several functionally-related clusters of relevance to cancer. The results demonstrate that public data derived from independent experiments can be used to inform biological research and support the development of molecular assays for probing the characteristics of a disease.
Cell cycle regulation by feed-forward loops coupling transcription and phosphorylation
Csikasz-Nagy, Attila; Kapuy, Orsolya; Toth, Attila; Pal, Csaba; Jensen, Lars Juhl; Uhlmann, Frank; Tyson, John J.; Novak, Bela (Nature Publishing Group, 2009-01-01)
The eukaryotic cell cycle requires precise temporal coordination of the activities of hundreds of ‘executor’ proteins (EPs) involved in cell growth and division. Cyclin-dependent protein kinases (Cdks) play central roles in regulating the production, activation, inactivation and destruction of these EPs. From genome-scale data sets of budding yeast, we identify 126 EPs that are regulated by Cdk1 both through direct phosphorylation of the EP and through phosphorylation of the transcription factors that control expression of the EP, so that each of these EPs is regulated by a feed-forward loop (FFL) from Cdk1. By mathematical modelling, we show that such FFLs can activate EPs at different phases of the cell cycle depending of the effective signs (+ or -) of the regulatory steps of the FFL.We provide several case studies of EPs that are controlled by FFLs exactly as our models predict. The signal-transduction properties of FFLs allow one (or a few) Cdk signal(s) to drive a host of cell cycle responses in correct temporal sequence.
Changes in poly(A) tail length dynamics from the loss of the circadian deadenylase Nocturnin
Kojima, Shihoko; Gendreau, Kerry L.; Sher-Chen, Elaine L.; Peng, Gao; Green, Carla B. (Nature, 2015-11-20)
mRNA poly(A) tails are important for mRNA stability and translation, and enzymes that regulate the poly(A) tail length significantly impact protein profiles. There are eleven putative deadenylases in mammals, and it is thought that each targets specific transcripts, although this has not been clearly demonstrated. Nocturnin (NOC) is a unique deadenylase with robustly rhythmic expression and loss of Noc in mice (Noc KO) results in resistance to diet-induced obesity. In an attempt to identify target transcripts of NOC, we performed “poly(A)denylome” analysis, a method that measures poly(A) tail length of transcripts in a global manner, and identified 213 transcripts that have extended poly(A) tails in Noc KO liver. These transcripts share unexpected characteristics: they are short in length, have long half-lives, are actively translated, and gene ontology analyses revealed that they are enriched in functions in ribosome and oxidative phosphorylation pathways. However, most of these transcripts do not exhibit rhythmicity in poly(A) tail length or steady-state mRNA level, despite Noc’s robust rhythmicity. Therefore, even though the poly(A) tail length dynamics seen between genotypes may not result from direct NOC deadenylase activity, these data suggest that NOC exerts strong effects on physiology through direct and indirect control of target mRNAs.
Chromosome mis-segregation and cytokinesis failure in trisomic human cells
Nicholson, Joshua M.; Macedo, Joana C.; Mattingly, Aaron J.; Wangsa, Darawalee; Camps, Jordi; Lima, Vera; Gomes, Ana M.; Doria, Sofia; Ried, Thomas; Logarinho, Elsa; Cimini, Daniela (eLife, 2015-05-05)
Cancer cells display aneuploid karyotypes and typically mis-segregate chromosomes at high rates, a phenotype referred to as chromosomal instability (CIN). To test the effects of aneuploidy on chromosome segregation and other mitotic phenotypes we used the colorectal cancer cell line DLD1 (2n = 46) and two variants with trisomy 7 or 13 (DLD1+7 and DLD1+13), as well as euploid and trisomy 13 amniocytes (AF and AF+13). We found that trisomic cells displayed higher rates of chromosome mis-segregation compared to their euploid counterparts. Furthermore, cells with trisomy 13 displayed a distinctive cytokinesis failure phenotype. We showed that up-regulation of SPG20 expression, brought about by trisomy 13 in DLD1+13 and AF+13 cells, is sufficient for the cytokinesis failure phenotype. Overall, our study shows that aneuploidy can induce chromosome mis-segregation. Moreover, we identified a trisomy 13-specific mitotic phenotype that is driven by up-regulation of a gene encoded on the aneuploid chromosome.
Comparative Metabolomics of Fruits and Leaves in a Hyperdiverse Lineage Suggests Fruits Are a Key Incubator of Phytochemical Diversification
Schneider, Gerald F.; Salazar, Diego; Hildreth, Sherry B.; Helm, Richard F.; Whitehead, Susan R. (Frontiers, 2021-08-30)
Interactions between plants and leaf herbivores have long been implicated as the major driver of plant secondary metabolite diversity. However, other plant-animal interactions, such as those between fruits and frugivores, may also be involved in phytochemical diversification. Using 12 species of Piper, we conducted untargeted metabolomics and molecular networking with extracts of fruits and leaves. We evaluated organ-specific secondary metabolite composition and compared multiple dimensions of phytochemical diversity across organs, including richness, structural complexity, and variability across samples at multiple scales within and across species. Plant organ identity, species identity, and the interaction between the two all significantly influenced secondary metabolite composition. Leaves and fruit shared a majority of compounds, but fruits contained more unique compounds and had higher total estimated chemical richness. While the relative levels of chemical richness and structural complexity across organs varied substantially across species, fruit diversity exceeded leaf diversity in more species than the reverse. Furthermore, the variance in chemical composition across samples was higher for fruits than leaves. By documenting a broad pattern of high phytochemical diversity in fruits relative to leaves, this study lays groundwork for incorporating fruit into a comprehensive and integrative understanding of the ecological and evolutionary factors shaping secondary metabolite composition at the whole-plant level.
The complete genome sequence of Staphylothermus marinus reveals differences in sulfur metabolism among heterotrophic Crenarchaeota
Anderson, Iain J.; Dharmarajan, Lakshmi; Rodriguez, Jason; Hooper, Sean; Porat, Iris; Ulrich, Luke E.; Elkins, James G.; Mavromatis, Kostas; Sun, Hui; Land, Miriam; Lapidus, Alla; Lucas, Susan; Barry, Kerrie W.; Huber, Harald; Zhulin, Igor B.; Whitman, William B.; Mukhopadhyay, Biswarup; Woese, Carl; Bristow, James; Kyrpides, Nikos C. (2009-04-02)
Background Staphylothermus marinus is an anaerobic, sulfur-reducing peptide fermenter of the archaeal phylum Crenarchaeota. It is the third heterotrophic, obligate sulfur reducing crenarchaeote to be sequenced and provides an opportunity for comparative analysis of the three genomes. Results The 1.57 Mbp genome of the hyperthermophilic crenarchaeote Staphylothermus marinus has been completely sequenced. The main energy generating pathways likely involve 2-oxoacid:ferredoxin oxidoreductases and ADP-forming acetyl-CoA synthases. S. marinus possesses several enzymes not present in other crenarchaeotes including a sodium ion-translocating decarboxylase likely to be involved in amino acid degradation. S. marinus lacks sulfur-reducing enzymes present in the other two sulfur-reducing crenarchaeotes that have been sequenced - Thermofilum pendens and Hyperthermus butylicus. Instead it has three operons similar to the mbh and mbx operons of Pyrococcus furiosus, which may play a role in sulfur reduction and/or hydrogen production. The two marine organisms, S. marinus and H. butylicus, possess more sodium-dependent transporters than T. pendens and use symporters for potassium uptake while T. pendens uses an ATP-dependent potassium transporter. T. pendens has adapted to a nutrient-rich environment while H. butylicus is adapted to a nutrient-poor environment, and S. marinus lies between these two extremes. Conclusion The three heterotrophic sulfur-reducing crenarchaeotes have adapted to their habitats, terrestrial vs. marine, via their transporter content, and they have also adapted to environments with differing levels of nutrients. Despite the fact that they all use sulfur as an electron acceptor, they are likely to have different pathways for sulfur reduction.
Computational approaches for discovery of common immunomodulators in fungal infections: towards broad-spectrum immunotherapeutic interventions
Kidane, Yared H.; Lawrence, Christopher B.; Murali, T. M. (2013-10-07)
Background Fungi are the second most abundant type of human pathogens. Invasive fungal pathogens are leading causes of life-threatening infections in clinical settings. Toxicity to the host and drug-resistance are two major deleterious issues associated with existing antifungal agents. Increasing a host’s tolerance and/or immunity to fungal pathogens has potential to alleviate these problems. A host’s tolerance may be improved by modulating the immune system such that it responds more rapidly and robustly in all facets, ranging from the recognition of pathogens to their clearance from the host. An understanding of biological processes and genes that are perturbed during attempted fungal exposure, colonization, and/or invasion will help guide the identification of endogenous immunomodulators and/or small molecules that activate host-immune responses such as specialized adjuvants. Results In this study, we present computational techniques and approaches using publicly available transcriptional data sets, to predict immunomodulators that may act against multiple fungal pathogens. Our study analyzed data sets derived from host cells exposed to five fungal pathogens, namely, Alternaria alternata, Aspergillus fumigatus, Candida albicans, Pneumocystis jirovecii, and Stachybotrys chartarum. We observed statistically significant associations between host responses to A. fumigatus and C. albicans. Our analysis identified biological processes that were consistently perturbed by these two pathogens. These processes contained both immune response-inducing genes such as MALT1, SERPINE1, ICAM1, and IL8, and immune response-repressing genes such as DUSP8, DUSP6, and SPRED2. We hypothesize that these genes belong to a pool of common immunomodulators that can potentially be activated or suppressed (agonized or antagonized) in order to render the host more tolerant to infections caused by A. fumigatus and C. albicans. Conclusions Our computational approaches and methodologies described here can now be applied to newly generated or expanded data sets for further elucidation of additional drug targets. Moreover, identified immunomodulators may be used to generate experimentally testable hypotheses that could help in the discovery of broad-spectrum immunotherapeutic interventions. All of our results are available at the following supplementary website: http://bioinformatics.cs.vt.edu/~murali/supplements/2013-kidane-bmc
Concept inventory development reveals common student misconceptions about microbiology
Briggs, Amy G.; Hughes, Lee E.; Brennan, Robert E.; Buchner, John; Horak, Rachel E. A.; Katz Amburn, D. Sue; McDonald, Ann H.; Primm, Todd P.; Smith, Ann C.; Stevens, Ann M.; Yung, Sunny B.; Paustian, Timothy D. (American Society for Microbiology, 2017-10)
Correction: Mitotic-Chromosome-Based Physical Mapping of the Culex quinquefasciatus Genome
Naumenko, Anastasia N.; Timoshevskiy, Vladimir A.; Kinney, Nicholas A.; Kokhanenko, Alina A.; deBruyn, Becky S.; Lovin, Diane D.; Stegniy, Vladimir N.; Severson, David W.; Sharakhov, Igor V.; Sharakhova, Maria V. (2015)
Correction
Critical role of deadenylation in regulating poly(A) rhythms and circadian gene expression
Yao, Xiangyu; Kojima, Shihoko; Chen, Jing (2020-04)
The mammalian circadian clock is deeply rooted in rhythmic regulation of gene expression. Rhythmic transcriptional control mediated by the circadian transcription factors is thought to be the main driver of mammalian circadian gene expression. However, mounting evidence has demonstrated the importance of rhythmic post-transcriptional controls, and it remains unclear how the transcriptional and post-transcriptional mechanisms collectively control rhythmic gene expression. In mouse liver, hundreds of genes were found to exhibit rhythmicity in poly(A) tail length, and the poly(A) rhythms are strongly correlated with the protein expression rhythms. To understand the role of rhythmic poly(A) regulation in circadian gene expression, we constructed a parsimonious model that depicts rhythmic control imposed upon basic mRNA expression and poly(A) regulation processes, including transcription, deadenylation, polyadenylation, and degradation. The model results reveal the rhythmicity in deadenylation as the strongest contributor to the rhythmicity in poly(A) tail length and the rhythmicity in the abundance of the mRNA subpopulation with long poly(A) tails (a rough proxy for mRNA translatability). In line with this finding, the model further shows that the experimentally observed distinct peak phases in the expression of deadenylases, regardless of other rhythmic controls, can robustly cluster the rhythmic mRNAs by their peak phases in poly(A) tail length and abundance of the long-tailed subpopulation. This provides a potential mechanism to synchronize the phases of target gene expression regulated by the same deadenylases. Our findings highlight the critical role of rhythmic deadenylation in regulating poly(A) rhythms and circadian gene expression. Author summary The biological circadian clock aligns bodily functions to the day-and-night cycle and is important for maintaining health. The rhythms in various biological processes ultimately stem from rhythmic gene expression in each single cell. Because several proteins in the mammalian core clock machinery are transcription factors, studies of mammalian circadian gene expression have focused on rhythmic transcriptional control. However, many recent studies have suggested the importance of rhythmic post-transcriptional controls. Here we use mathematical modeling to investigate how transcriptional and post-transcriptional rhythms jointly control rhythmic gene expression. We particularly focus on rhythmic post-transcriptional regulation of the mRNA poly(A) tail, a nearly universal feature of mRNAs which controls mRNA stability and translation. Our model reveals that the rhythmicities in poly(A) tail length and mRNA translatability are most strongly affected by the rhythmicity in deadenylation, the process that shortens the poly(A) tail. Particularly, the phases of poly(A) tail length and mRNA translatability are dominated by the phase of deadenylation. In light of our findings, rhythmic control of deadenylation deserves greater future attention in the field of circadian gene expression.
Development, validation and application of the Microbiology Concept Inventory
Paustian, T. D.; Briggs, A. G.; Brennan, R. E.; Boury, N.; Buchner, J.; Harris, S.; Horak, R. E. A.; Hughes, Lee E.; Katz Amburn, D. Sue; Massimelli, M. J.; McDonald, A. H.; Primm, T. P.; Smith, A. C.; Stevens, Ann M.; Yung, S. B. (American Society for Microbiology, 2017-10)
Divergent age-dependent peripheral immune transcriptomic profile following traumatic brain injury
Hazy, Amanda; Bochicchio, Lauren; Oliver, Andrea; Xie, Eric; Geng, Shuo; Brickler, Thomas; Xie, Hehuang David; Li, Liwu; Allen, Irving C.; Theus, Michelle H. (Springer Nature, 2019-06-12)
The peripheral immune system is a major regulator of the pathophysiology associated with traumatic brain injury (TBI). While age-at-injury influences recovery from TBI, the differential effects on the peripheral immune response remain unknown. Here, we investigated the effects of TBI on gene expression changes in murine whole blood using RNAseq analysis, gene ontology and network topology-based key driver analysis. Genome-wide comparison of CCI-injured peripheral whole blood showed a significant increase in genes involved in proteolysis and oxidative-reduction processes in juvenile compared to adult. Conversely, a greater number of genes, involved in migration, cytokine-mediated signaling and adhesion, were found reduced in CCI-injured juvenile compared to CCI-injured adult immune cells. Key driver analysis also identified G-protein coupled and novel pattern recognition receptor (PRR), P2RY10, as a central regulator of these genes. Lastly, we found Dectin-1, a c-type lectin PRR to be reduced at the protein level in both naive neutrophils and on infiltrating immune cells in the CCI-injured juvenile cortex. These findings demonstrate a distinct peripheral inflammatory profile in juvenile mice, which may impact the injury and repair response to brain trauma.
Dynamic Alu Methylation during Normal Development, Aging, and Tumorigenesis
Luo, Yanting; Lu, Xuemei; Xie, Hehuang David (Hindawi, 2014-08-27)
DNA methylation primarily occurs on CpG dinucleotides and plays an important role in transcriptional regulations during tissue development and cell differentiation. Over 25% of CpG dinucleotides in the human genome reside within Alu elements, the most abundant human repeats. The methylation of Alu elements is an important mechanism to suppress Alu transcription and subsequent retrotransposition. Decades of studies revealed that Alu methylation is highly dynamic during early development and aging. Recently, many environmental factors were shown to have a great impact on Alu methylation. In addition, aberrant Alu methylation has been documented to be an early event in many tumors and Alu methylation levels have been associated with tumor aggressiveness. The assessment of the Alu methylation has become an important approach for early diagnosis and/or prognosis of cancer. This review focuses on the dynamic Alu methylation during development, aging, and tumor genesis. The cause and consequence of Alu methylation changes will be discussed.
Dynamical Localization of DivL and PleC in the Asymmetric Division Cycle of Caulobacter crescentus: A Theoretical Investigation of Alternative Models
Subramanian, Kartik; Paul, Mark R.; Tyson, John J. (PLOS, 2015-07-01)
Cell-fate asymmetry in the predivisional cell of Caulobacter crescentus requires that the regulatory protein DivL localizes to the new pole of the cell where it up-regulates CckA kinase, resulting in a gradient of CtrA~P across the cell. In the preceding stage of the cell cycle (the “stalked” cell), DivL is localized uniformly along the cell membrane and maintained in an inactive form by DivK~P. It is unclear how DivL overcomes inhibition by DivK~P in the predivisional cell simply by changing its location to the new pole. It has been suggested that co-localization of DivL with PleC phosphatase at the new pole is essential to DivL’s activity there. However, there are contrasting views on whether the bifunctional enzyme, PleC, acts as a kinase or phosphatase at the new pole. To explore these ambiguities, we formulated a mathematical model of the spatiotemporal distributions of DivL, PleC and associated proteins (DivJ, DivK, CckA, and CtrA) during the asymmetric division cycle of a Caulobacter cell. By varying localization profiles of DivL and PleC in our model, we show how the physiologically observed spatial distributions of these proteins are essential for the transition from a stalked cell to a predivisional cell. Our simulations suggest that PleC is a kinase in predivisional cells, and that, by sequestering DivK~P, the kinase form of PleC enables DivL to be reactivated at the new pole. Hence, co-localization of PleC kinase and DivL is essential to establishing cellular asymmetry. Our simulations reproduce the experimentally observed spatial distribution and phosphorylation status of CtrA in wild-type and mutant cells. Based on the model, we explore novel combinations of mutant alleles, making predictions that can be tested experimentally.
EGR1 recruits TET1 to shape the brain methylome during development and upon neuronal activity
Sun, Zhixiong; Xu, Xiguang; He, Jianlin; Murray, Alexander; Sun, Ming-an; Wei, Xiaoran; Wang, Xia; McCoig, Emmarose; Xie, Evan; Jiang, Xi; Li, Liwu; Zhu, Jinsong; Chen, Jianjun; Morozov, Alexei; Pickrell, Alicia M.; Theus, Michelle H.; Xie, Hehuang David (2019-08-29)
Life experience can leave lasting marks, such as epigenetic changes, in the brain. How life experience is translated into storable epigenetic information remains largely unknown. With unbiased data-driven approaches, we predicted that Egr1, a transcription factor important for memory formation, plays an essential role in brain epigenetic programming. We performed EGR1 ChIP-seq and validated thousands of EGR1 binding sites with methylation patterns established during postnatal brain development. More specifically, these EGR1 binding sites become hypomethylated in mature neurons but remain heavily methylated in glia. We further demonstrated that EGR1 recruits a DNA demethylase TET1 to remove the methylation marks and activate downstream genes. The frontal cortices from the knockout mice lacking Egr1 or Tet1 share strikingly similar profiles in both gene expression and DNA methylation. In summary, our study reveals EGR1 programs the brain methylome together with TET1 providing new insight into how life experience may shape the brain methylome.
EGR2 is elevated and positively regulates inflammatory IFNγ production in lupus CD4+ T cells
Dai, Rujuan; Heid, Bettina; Xu, Xiguang; Xie, Hehuang David; Reilly, Christopher M.; Ahmed, Sattar Ansar (2020-07-09)
Background Recent studies have shown that early growth response 2 (EGR2) is highly induced in activated T cells and regulates T cell functions. In normal C57BL/6 (B6) mice, deletion of EGR2 in lymphocytes results in the development of lupus-like systemic autoimmune disease, which implies indirectly an autoimmune protective role of EGR2. Conversely, increased EGR2 gene expression is suggested to link with high risk of human lupus. In the present studies we sought to clarify the expression and inflammation regulatory role of EGR2 in murine lupus T cells directly. Results We performed RT-qPCR analysis and found a significant increase of EGR2 mRNA expression in human lupus PBMCs and in CD4+ T cells from three different murine lupus models including MRL-lpr, B6-lpr, and B6.sle123 mice at diseased stage when compared to age-matched control MRL or B6 mice. By performing intracellular flow cytometry analysis, we found that EGR2 protein expression was significantly increased in resting lupus (either MRL-lpr or B6.sle123) CD4+ T cells when compared to CD4+ T cells from their respective non-autoimmune controls. However, there was no difference of EGR2 protein expression in anti-CD3 and anti-CD28 stimulated control and lupus CD4+ T cells since there was a stronger induction of EGR2 in activated control CD4+ T cells. EGR2 expression was significantly increased in MRL-lpr mice at an age when lupus is manifested. To understand further the function of elevated EGR2 in lupus CD4+ T cells, we inhibited EGR2 with a specific siRNA in vitro in splenocytes from MRL-lpr and control MRL mice at 15 weeks-of-age. We found that EGR2 inhibition significantly reduced IFNγ production in PMA and ionomycin activated MRL-lpr lupus CD4+ T cells, but not control MRL CD4+ T cells. We also found that inhibition of EGR2 in vitro suppressed the Th1 differentiation in both MRL and MRL-lpr naïve CD4+ T cells. Conclusions EGR2 is highly upregulated in human and murine lupus cells. Our in vitro data suggest a positive role of EGR2 in the regulation of Th1 differentiation and IFNγ production in lupus effector CD4+ T cells.

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