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26.  Mechanotransduction: use the force(s) 
BMC Biology  2015;13:47.
Mechanotransduction - how cells sense physical forces and translate them into biochemical and biological responses - is a vibrant and rapidly-progressing field, and is important for a broad range of biological phenomena. This forum explores the role of mechanotransduction in a variety of cellular activities and highlights intriguing questions that deserve further attention.
PMCID: PMC4491211  PMID: 26141078
27.  Models in biology: lessons from modeling regulation of the eukaryotic cell cycle 
BMC Biology  2015;13:46.
In this essay we illustrate some general principles of mathematical modeling in biology by our experiences in studying the molecular regulatory network underlying eukaryotic cell division. We discuss how and why the models moved from simple, parsimonious cartoons to more complex, detailed mechanisms with many kinetic parameters. We describe how the mature models made surprising and informative predictions about the control system that were later confirmed experimentally. Along the way, we comment on the ‘parameter estimation problem’ and conclude with an appeal for a greater role for mathematical models in molecular cell biology.
PMCID: PMC4486427  PMID: 26129844
Mathematical models; Mitosis-promoting factor; Cell cycle checkpoints; Regulated kinases; Regulated phosphatases; Regulated proteolysis
28.  Detection of Escherichia albertii from chicken meat and giblets 
Escherichia albertii occasionally causes food-borne outbreaks of gastroenteritis in humans; however, little is known about the vehicle of transmission. To screen retail chicken products for the presence of E. albertii, 104 retail chicken products were investigated. Portions of enrichment cultures that were PCR-positive for E. albertii (n=3) were sub-cultured on agar medium. Only 2 strains obtained from 2 chicken giblet samples were identified as E. albertii by multi locus sequence typing. Antimicrobial susceptibility testing showed that 1 strain was resistant to streptomycin and sulfisoxazole. Both strains harbored the virulence genes cdt and eae. This study is the first description of E. albertii isolation from retail food, suggesting that chicken products are a potential vehicle of E. albertii transmission.
PMCID: PMC4527513  PMID: 25754935
chicken giblet; chicken meat; chicken products; Escherichia albertii; infection source
29.  Coding of Electronic Laboratory Reports for Biosurveillance, Selected United States Hospitals, 2011 
Electronic laboratory reporting has been promoted as a public health priority. The Office of the U.S. National Coordinator for Health Information Technology has endorsed two coding systems: Logical Observation Identifiers Names and Codes (LOINC) for laboratory test orders and Systemized Nomenclature of Medicine-Clinical Terms (SNOMED CT) for test results.
Materials and Methods
We examined LOINC and SNOMED CT code use in electronic laboratory data reported in 2011 by 63 non-federal hospitals to BioSense electronic syndromic surveillance system. We analyzed the frequencies, characteristics, and code concepts of test orders and results.
A total of 14,028,774 laboratory test orders or results were reported. No test orders used SNOMED CT codes. To describe test orders, 77% used a LOINC code, 17% had no value, and 6% had a non-informative value, “OTH”. Thirty-three percent (33%) of test results had missing or non-informative codes. For test results with at least one informative value, 91.8% had only LOINC codes, 0.7% had only SNOMED codes, and 7.4% had both. Of 108 SNOMED CT codes reported without LOINC codes, 45% could be matched to at least one LOINC code.
Missing or non-informative codes comprised almost a quarter of laboratory test orders and a third of test results reported to BioSense by non-federal hospitals. Use of LOINC codes for laboratory test results was more common than use of SNOMED CT. Complete and standardized coding could improve the usefulness of laboratory data for public health surveillance and response.
PMCID: PMC4576438  PMID: 26392850
Logical Observation Identifiers Names and Codes (LOINC); Systemized Nomenclature of Medicine Clinical Terms (SNOMED CT); electronic laboratory report; computerized medical record systems; biosurveillance
30.  Q&A: How do plants sense and respond to UV-B radiation? 
BMC Biology  2015;13:45.
Plants are able to sense UV-B through the UV-B photoreceptor UVR8. UV-B photon absorption by a UVR8 homodimer leads to UVR8 monomerization and interaction with the downstream signaling factor COP1. This then initiates changes in gene expression, which lead to several metabolic and morphological alterations. A major response is the activation of mechanisms associated with UV-B acclimation and UV-B tolerance, including biosynthesis of sunscreen metabolites, antioxidants and DNA repair enzymes. To balance the response, UVR8 is inactivated by regulated re-dimerization. Apart from their importance for plants, UVR8 and its interacting protein COP1 have already proved useful for the optogenetic toolkit used to engineer synthetic light-dependent responses.
PMCID: PMC4484705  PMID: 26123292
31.  Sexual conflict maintains variation at an insecticide resistance locus 
BMC Biology  2015;13:34.
The maintenance of genetic variation through sexually antagonistic selection is controversial, partly because specific sexually-antagonistic alleles have not been identified. The Drosophila DDT resistance allele (DDT-R) is an exception. This allele increases female fitness, but simultaneously decreases male fitness, and it has been suggested that this sexual antagonism could explain why polymorphism was maintained at the locus prior to DDT use. We tested this possibility using a genetic model and then used evolving fly populations to test model predictions.
Theory predicted that sexual antagonism is able to maintain genetic variation at this locus, hence explaining why DDT-R did not fix prior to DDT use despite increasing female fitness, and experimentally evolving fly populations verified theoretical predictions.
This demonstrates that sexually antagonistic selection can maintain genetic variation and explains the DDT-R frequencies observed in nature.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-015-0143-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4484701  PMID: 26032845
32.  The role of juvenile hormone and insulin/TOR signaling in the growth of Manduca sexta 
BMC Biology  2015;13:44.
In many insect species, fitness trade-offs exist between maximizing body size and developmental speed. Understanding how various species evolve different life history strategies requires knowledge of the physiological mechanisms underlying the regulation of body size and developmental timing. Here the roles of juvenile hormone (JH) and insulin/target of rapamycin (TOR) signaling in the regulation of the final body size were examined in the tobacco hornworm, Manduca sexta.
Feeding rapamycin to wild-type larvae decreased the growth rate but did not alter the peak size of the larvae. In contrast, feeding rapamycin to the JH-deficient black mutant larvae caused the larvae to significantly increase the peak size relative to the DMSO-fed control animals by lengthening the terminal growth period. Furthermore, the critical weight was unaltered by feeding rapamycin, indicating that in Manduca, the critical weight is not influenced by insulin/TOR signaling. In addition, post-critical weight starved black mutant Manduca given rapamycin underwent metamorphosis sooner than those that were fed, mimicking the “bail-out mechanism”.
Our study demonstrates that JH masks the effects of insulin/TOR signaling in the determination of the final body size and that the critical weights in Drosophila and Manduca rely on distinct mechanisms that reflect different life history strategies. Our study also suggests that TOR signaling lengthens the terminal growth period in Manduca as it does in Drosophila, and that JH levels determine the relative contributions of nutrient- and body size-sensing pathways to metamorphic timing.
PMCID: PMC4499214  PMID: 26108483
Developmental timing; Critical weight; Life history trade-offs; Manduca sexta; Drosophila melanogaster; Metamorphosis; Insulin/TOR signaling; Juvenile hormone; Prothoracic gland; Molt timer
33.  Shell neurons of the master circadian clock coordinate the phase of tissue clocks throughout the brain and body 
BMC Biology  2015;13:43.
Daily rhythms in mammals are programmed by a master clock in the suprachiasmatic nucleus (SCN). The SCN contains two main compartments (shell and core), but the role of each region in system-level coordination remains ill defined. Herein, we use a functional assay to investigate how downstream tissues interpret region-specific outputs by using in vivo exposure to long day photoperiods to temporally dissociate the SCN. We then analyze resulting changes in the rhythms of clocks located throughout the brain and body to examine whether they maintain phase synchrony with the SCN shell or core.
Nearly all of the 17 tissues examined in the brain and body maintain phase synchrony with the SCN shell, but not the SCN core, which indicates that downstream oscillators are set by cues controlled specifically by the SCN shell. Interestingly, we also found that SCN dissociation diminished the amplitude of rhythms in core clock gene and protein expression in brain tissues by 50–75 %, which suggests that light-driven changes in the functional organization of the SCN markedly influence the strength of rhythms in downstream tissues.
Overall, our results reveal that body clocks receive time-of-day cues specifically from the SCN shell, which may be an adaptive design principle that serves to maintain system-level phase relationships in a changing environment. Further, we demonstrate that lighting conditions alter the amplitude of the molecular clock in downstream tissues, which uncovers a new form of plasticity that may contribute to seasonal changes in physiology and behavior.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-015-0157-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4489020  PMID: 26099272
Circadian; Coupling; Peripheral and central oscillators; Photoperiod; Suprachiasmatic nucleus
34.  Sequencing strategies and characterization of 721 vervet monkey genomes for future genetic analyses of medically relevant traits 
BMC Biology  2015;13:41.
We report here the first genome-wide high-resolution polymorphism resource for non-human primate (NHP) association and linkage studies, constructed for the Caribbean-origin vervet monkey, or African green monkey (Chlorocebus aethiops sabaeus), one of the most widely used NHPs in biomedical research. We generated this resource by whole genome sequencing (WGS) of monkeys from the Vervet Research Colony (VRC), an NIH-supported research resource for which extensive phenotypic data are available.
We identified genome-wide single nucleotide polymorphisms (SNPs) by WGS of 721 members of an extended pedigree from the VRC. From high-depth WGS data we identified more than 4 million polymorphic unequivocal segregating sites; by pruning these SNPs based on heterozygosity, quality control filters, and the degree of linkage disequilibrium (LD) between SNPs, we constructed genome-wide panels suitable for genetic association (about 500,000 SNPs) and linkage analysis (about 150,000 SNPs). To further enhance the utility of these resources for linkage analysis, we used a further pruned subset of the linkage panel to generate multipoint identity by descent matrices.
The genetic and phenotypic resources now available for the VRC and other Caribbean-origin vervets enable their use for genetic investigation of traits relevant to human diseases.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-015-0152-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4494155  PMID: 26092298
Vervet; Non-human primate; Whole genome sequencing; SNP; Linkage; Association
35.  Lhx8 regulates primordial follicle activation and postnatal folliculogenesis 
BMC Biology  2015;13:39.
The early stages of ovarian follicle formation—beginning with the breakdown of germ cell cysts and continuing with the formation of primordial follicles and transition to primary and secondary follicles—are critical in determining reproductive life span and fertility. Previously, we discovered that global knockouts of germ cell-specific transcriptional co-regulators Sohlh1, Sohlh2, Lhx8, and Nobox, cause rapid oocyte loss and ovarian failure. Also factors such as Nobox and Sohlh1 are associated with human premature ovarian failure. In this study, we developed a conditional knockout of Lhx8 to study oocyte-specific pathways in postnatal folliculogenesis.
The conditional deficiency of Lhx8 in the oocytes of primordial follicles leads to massive primordial oocyte activation, in part, by indirectly interacting with the PI3K-AKT pathway, as shown by synergistic effects on FOXO3 nucleocytoplasmic translocation and rpS6 activation. However, LHX8 does not directly regulate members of the PI3K-AKT pathway; instead, we show that LHX8 represses Lin28a expression, a known regulator of mammalian metabolism and of the AKT/mTOR pathway. LHX8 can bind to the Lin28a promoter, and the depletion of Lin28a in Lhx8-deficient oocytes partially suppresses primordial oocyte activation. Moreover, unlike the PI3K-AKT pathway, LHX8 is critical beyond primordial follicle activation, and blocks the primary to secondary follicle transition.
Our results indicate that the LHX8-LIN28A pathway is essential in the earliest stages of primordial follicle activation, and LHX8 is an important oocyte-specific transcription factor in the ovary for regulating postnatal folliculogenesis.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-015-0151-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4487509  PMID: 26076587
Lhx8; Primordial follicle; Oocyte; Lin28a; Ovarian reserve
36.  Layering genetic circuits to build a single cell, bacterial half adder 
BMC Biology  2015;13:40.
Gene regulation in biological systems is impacted by the cellular and genetic context-dependent effects of the biological parts which comprise the circuit. Here, we have sought to elucidate the limitations of engineering biology from an architectural point of view, with the aim of compiling a set of engineering solutions for overcoming failure modes during the development of complex, synthetic genetic circuits.
Using a synthetic biology approach that is supported by computational modelling and rigorous characterisation, AND, OR and NOT biological logic gates were layered in both parallel and serial arrangements to generate a repertoire of Boolean operations that include NIMPLY, XOR, half adder and half subtractor logics in a single cell. Subsequent evaluation of these near-digital biological systems revealed critical design pitfalls that triggered genetic context-dependent effects, including 5′ UTR interferences and uncontrolled switch-on behaviour of the supercoiled σ54 promoter. In particular, the presence of seven consecutive hairpins immediately downstream of the promoter transcription start site severely impeded gene expression.
As synthetic biology moves forward with greater focus on scaling the complexity of engineered genetic circuits, studies which thoroughly evaluate failure modes and engineering solutions will serve as important references for future design and development of synthetic biological systems. This work describes a representative case study for the debugging of genetic context-dependent effects through principles elucidated herein, thereby providing a rational design framework to integrate multiple genetic circuits in a single prokaryotic cell.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-015-0146-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4490610  PMID: 26078033
37.  DNA transposons have colonized the genome of the giant virus Pandoravirus salinus 
BMC Biology  2015;13:38.
Transposable elements are mobile DNA sequences that are widely distributed in prokaryotic and eukaryotic genomes, where they represent a major force in genome evolution. However, transposable elements have rarely been documented in viruses, and their contribution to viral genome evolution remains largely unexplored. Pandoraviruses are recently described DNA viruses with genome sizes that exceed those of some prokaryotes, rivaling parasitic eukaryotes. These large genomes appear to include substantial noncoding intergenic spaces, which provide potential locations for transposable element insertions. However, no mobile genetic elements have yet been reported in pandoravirus genomes.
Here, we report a family of miniature inverted-repeat transposable elements (MITEs) in the Pandoravirus salinus genome, representing the first description of a virus populated with a canonical transposable element family that proliferated by transposition within the viral genome. The MITE family, which we name Submariner, includes 30 copies with all the hallmarks of MITEs: short length, terminal inverted repeats, TA target site duplication, and no coding capacity. Submariner elements show signs of transposition and are undetectable in the genome of Pandoravirus dulcis, the closest known relative Pandoravirus salinus. We identified a DNA transposon related to Submariner in the genome of Acanthamoeba castellanii, a species thought to host pandoraviruses, which contains remnants of coding sequence for a Tc1/mariner transposase. These observations suggest that the Submariner MITEs of P. salinus belong to the widespread Tc1/mariner superfamily and may have been mobilized by an amoebozoan host. Ten of the 30 MITEs in the P. salinus genome are located within coding regions of predicted genes, while others are close to genes, suggesting that these transposons may have contributed to viral genetic novelty.
Our discovery highlights the remarkable ability of DNA transposons to colonize and shape genomes from all domains of life, as well as giant viruses. Our findings continue to blur the division between viral and cellular genomes, adhering to the emerging view that the content, dynamics, and evolution of the genomes of giant viruses do not substantially differ from those of cellular organisms.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-015-0145-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4495683  PMID: 26067596
Genome evolution; Miniature inverted-repeat transposable element (MITE); Virus
38.  Emerging role of transcription factor-microRNA-target gene feed-forward loops in cancer 
Biomedical Reports  2015;3(5):611-616.
Transcriptional regulatory networks are biological network motifs that act in accordance with each other to play decisive roles in the pathological processes of cancer. One of the most common types, the feed-forward loop (FFL), has recently attracted interest. Three connected deregulated nodes, a transcription factor (TF), its downstream microRNA (miRNA) and their shared target gene can make up a class of cancer-involved FFLs as ≥1 of the 3 can act individually as a bona fide oncogene or a tumor suppressor. Numerous notable elements, such as p53, miR-17-92 cluster and cyclins, are proven members of their respective FFLs. Databases of interaction prediction, verification of experimental methods and confirmation of loops have been continually emerging during recent years. Development of TF-miRNA-target loops may help understand the mechanism of tumorgenesis at a higher level and explain the discovery and screening of the therapeutic target for drug exploitation.
PMCID: PMC4535151  PMID: 26405533
feed-forward loop; transcription factor; microRNA; cancer
39.  The initiation of nocturnal dormancy in Synechococcus as an active process 
BMC Biology  2015;13:36.
Most organisms, especially photoautotrophs, alter their behaviours in response to day–night alternations adaptively because of their great reliance on light. Upon light-to-dark transition, dramatic and universal decreases in transcription level of the majority of the genes in the genome of the unicellular cyanobacterium, Synechococcus elongatus PCC 7942 are observed. Because Synechococcus is an obligate photoautotroph, it has been generally assumed that repression of the transcription in the dark (dark repression) would be caused by a nocturnal decrease in photosynthetic activities through the reduced availability of energy (e.g. adenosine triphosphate (ATP)) needed for mRNA synthesis.
However, against this general assumption, we obtained evidence that the rapid and dynamic dark repression is an active process. Although the addition of photosynthesis inhibitors to cells exposed to light mimicked transcription profiles in the dark, it did not significantly affect the cellular level of ATP. By contrast, when ATP levels were decreased by the inhibition of both photosynthesis and respiration, the transcriptional repression was attenuated through inhibition of RNA degradation. This observation indicates that Synechococcus actively downregulates genome-wide transcription in the dark. Even though the level of total mRNA dramatically decreased in the dark, Synechococcus cells were still viable, and they do not need de novo transcription for their survival in the dark for at least 48 hours.
Dark repression appears to enable cells to enter into nocturnal dormancy as a feed-forward process, which would be advantageous for their survival under periodic nocturnal conditions.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-015-0144-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4494158  PMID: 26058805
Cyanobacteria; Light/Dark; Transcription; Feed-forward regulation
40.  Nuclear myosin 1 contributes to a chromatin landscape compatible with RNA polymerase II transcription activation 
BMC Biology  2015;13:35.
Nuclear myosin 1c (NM1) is emerging as a regulator of transcription and chromatin organization.
Using chromatin immunoprecipitation and deep sequencing (ChIP-Seq) in combination with molecular analyses, we investigated the global association of NM1 with the mammalian genome. Analysis of the ChIP-Seq data demonstrates that NM1 binds across the entire mammalian genome with occupancy peaks correlating with distributions of RNA Polymerase II (Pol II) and active epigenetic marks at class II gene promoters. In mouse embryonic fibroblasts subjected to RNAi mediated NM1 gene silencing, we show that NM1 synergizes with polymerase-associated actin to maintain active Pol II at the promoter. NM1 also co-localizes with the nucleosome remodeler SNF2h at class II promoters where they assemble together with WSTF as part of the B-WICH complex. A high resolution micrococcal nuclease (MNase) assay and quantitative real time PCR shows that this mechanism is required for local chromatin remodeling. Following B-WICH assembly, NM1 mediates physical recruitment of the histone acetyl transferase PCAF and the histone methyl transferase Set1/Ash2 to maintain and preserve H3K9acetylation and H3K4trimethylation for active transcription.
We propose a novel genome-wide mechanism where myosin synergizes with Pol II-associated actin to link the polymerase machinery with permissive chromatin for transcription activation.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-015-0147-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4486089  PMID: 26044184
RNA polymerase II transcription; NM1; Epigenetics; Genome-wide analysis
41.  Q&A: insulin secretion and type 2 diabetes: why do β-cells fail? 
BMC Biology  2015;13:33.
PMCID: PMC4435650  PMID: 25982967
42.  A dynamic evolutionary and functional landscape of plant phased small interfering RNAs 
BMC Biology  2015;13:32.
Secondary, phased small interfering RNAs (phasiRNAs) derived from protein-coding or noncoding loci (PHAS) are emerging as a new type of regulators of gene expression in plants. However, the evolution and function of these novel siRNAs in plant species remain largely unexplored.
We systematically analyzed PHAS loci in 23 plant species covering major phylogenetic groups spanning alga, moss, gymnosperm, basal angiosperm, monocot, and dicot. We identified over 3,300 PHAS loci, among which ~1,600 were protein-coding genes. Most of these PHAS loci were novel and clade- or species-specific and showed distinct expression patterns in association with particular development stages, viral infection, or abiotic stresses. Unexpectedly, numerous PHAS loci produced phasiRNAs from introns or exon–intron junction regions. Our comprehensive analysis suggests that phasiRNAs predominantly regulate protein-coding genes from which they are derived and genes from the same families of the phasiRNA-deriving genes, in contrast to the dominant trans-regulatory mode of miRNAs. The stochastic occurrence of many PHAS loci in the plant kingdom suggests their young evolutionary origins.
Our study discovered an unprecedented diversity of protein-coding genes that produce phasiRNAs in a wide variety of plants, and set a kingdom-wide foundation for investigating the novel roles of phasiRNAs in shaping phenotype diversities of plants.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-015-0142-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4457045  PMID: 25980406
Evolution; Function; Plant phasiRNAs; Protein-coding genes
43.  A chromatin code for alternative splicing involving a putative association between CTCF and HP1α proteins 
BMC Biology  2015;13:31.
Alternative splicing is primarily controlled by the activity of splicing factors and by the elongation of the RNA polymerase II (RNAPII). Recent experiments have suggested a new complex network of splicing regulation involving chromatin, transcription and multiple protein factors. In particular, the CCCTC-binding factor (CTCF), the Argonaute protein AGO1, and members of the heterochromatin protein 1 (HP1) family have been implicated in the regulation of splicing associated with chromatin and the elongation of RNAPII. These results raise the question of whether these proteins may associate at the chromatin level to modulate alternative splicing.
Using chromatin immunoprecipitation sequencing (ChIP-Seq) data for CTCF, AGO1, HP1α, H3K27me3, H3K9me2, H3K36me3, RNAPII, total H3 and 5metC and alternative splicing arrays from two cell lines, we have analyzed the combinatorial code of their binding to chromatin in relation to the alternative splicing patterns between two cell lines, MCF7 and MCF10. Using Machine Learning techniques, we identified the changes in chromatin signals that are most significantly associated with splicing regulation between these two cell lines. Moreover, we have built a map of the chromatin signals on the pre-mRNA, that is, a chromatin-based RNA-map, which can explain 606 (68.55%) of the regulated events between MCF7 and MCF10. This chromatin code involves the presence of HP1α, CTCF, AGO1, RNAPII and histone marks around regulated exons and can differentiate patterns of skipping and inclusion. Additionally, we found a significant association of HP1α and CTCF activities around the regulated exons and a putative DNA binding site for HP1α.
Our results show that a considerable number of alternative splicing events could have a chromatin-dependent regulation involving the association of HP1α and CTCF near regulated exons. Additionally, we find further evidence for the involvement of HP1α and AGO1 in chromatin-related splicing regulation.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-015-0141-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4446157  PMID: 25934638
Chromatin; Splicing; Histones; Splicing code
44.  Expression of leukemia inhibitory factor in Müller glia cells is regulated by a redox-dependent mRNA stability mechanism 
BMC Biology  2015;13:30.
Photoreceptor degeneration is a main hallmark of many blinding diseases making protection of photoreceptors crucial to prevent vision loss. Thus, regulation of endogenous neuroprotective factors may be key for cell survival and attenuation of disease progression. Important neuroprotective factors in the retina include H2O2 generated by injured photoreceptors, and leukemia inhibitory factor (LIF) expressed in Müller glia cells in response to photoreceptor damage.
We present evidence that H2O2 connects to the LIF response by inducing stabilization of Lif transcripts in Müller cells. This process was independent of active gene transcription and p38 MAPK, but relied on AU-rich elements (AREs), which we identified within the highly conserved Lif 3′UTR. Affinity purification combined with quantitative mass spectrometry identified several proteins that bound to these AREs. Among those, interleukin enhancer binding factor 3 (ILF3) was confirmed to participate in the redox-dependent Lif mRNA stabilization. Additionally we show that KH-type splicing regulatory protein (KHSRP) was crucial for maintaining basal Lif expression levels in non-stressed Müller cells.
Our results suggest that H2O2-induced redox signaling increases Lif transcript levels through ILF3 mediated mRNA stabilization. Generation of H2O2 by injured photoreceptors may thus enhance stability of Lif mRNA and therefore augment neuroprotective LIF signaling during degenerative conditions in vivo.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-015-0137-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4462110  PMID: 25907681
LIF; Redox signaling; mRNA stability; Retina; Müller glial cells; ILF3; KHSRP; p38 MAPK; Neuroprotection
45.  The study of Priapulus caudatus reveals conserved molecular patterning underlying different gut morphogenesis in the Ecdysozoa 
BMC Biology  2015;13:29.
The digestive systems of animals can become highly specialized in response to their exploration and occupation of new ecological niches. Although studies on different animals have revealed commonalities in gut formation, the model systems Caenorhabditis elegans and Drosophila melanogaster, which belong to the invertebrate group Ecdysozoa, exhibit remarkable deviations in how their intestines develop. Their morphological and developmental idiosyncrasies have hindered reconstructions of ancestral gut characters for the Ecdysozoa, and limit comparisons with vertebrate models. In this respect, the phylogenetic position, and slow evolving morphological and molecular characters of marine priapulid worms advance them as a key group to decipher evolutionary events that occurred in the lineages leading to C. elegans and D. melanogaster.
In the priapulid Priapulus caudatus, the gut consists of an ectodermal foregut and anus, and a mid region of at least partial endodermal origin. The inner gut develops into a 16-cell primordium devoid of visceral musculature, arranged in three mid tetrads and two posterior duplets. The mouth invaginates ventrally and shifts to a terminal anterior position as the ventral anterior ectoderm differentially proliferates. Contraction of the musculature occurs as the head region retracts into the trunk and resolves the definitive larval body plan. Despite obvious developmental differences with C. elegans and D. melanogaster, the expression in P. caudatus of the gut-related candidate genes NK2.1, foxQ2, FGF8/17/18, GATA456, HNF4, wnt1, and evx demonstrate three distinct evolutionarily conserved molecular profiles that correlate with morphologically identified sub-regions of the gut.
The comparative analysis of priapulid development suggests that a midgut formed by a single endodermal population of vegetal cells, a ventral mouth, and the blastoporal origin of the anus are ancestral features in the Ecdysozoa. Our molecular data on P. caudatus reveal a conserved ecdysozoan gut-patterning program and demonstrates that extreme morphological divergence has not been accompanied by major molecular innovations in transcriptional regulators during digestive system evolution in the Ecdysozoa. Our data help us understand the origins of the ecdysozoan body plan, including those of C. elegans and D. melanogaster, and this is critical for comparisons between these two prominent model systems and their vertebrate counterparts.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-015-0139-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4434581  PMID: 25895830
C. elegans; Drosophila; Ecdysozoa; Endoderm; Gut development; Hindgut; Mesoderm; Midgut; Mouth; Priapulid
46.  Dissection of jasmonate functions in tomato stamen development by transcriptome and metabolome analyses 
BMC Biology  2015;13:28.
Jasmonates are well known plant signaling components required for stress responses and development. A prominent feature of jasmonate biosynthesis or signaling mutants is the loss of fertility. In contrast to the male sterile phenotype of Arabidopsis mutants, the tomato mutant jai1-1 exhibits female sterility with additional severe effects on stamen and pollen development. Its senescence phenotype suggests a function of jasmonates in regulation of processes known to be mediated by ethylene. To test the hypothesis that ethylene involved in tomato stamen development is regulated by jasmonates, a temporal profiling of hormone content, transcriptome and metabolome of tomato stamens was performed using wild type and jai1-1.
Wild type stamens showed a transient increase of jasmonates that is absent in jai1-1. Comparative transcriptome analyses revealed a diminished expression of genes involved in pollen nutrition at early developmental stages of jai1-1 stamens, but an enhanced expression of ethylene-related genes at late developmental stages. This finding coincides with an early increase of the ethylene precursor 1-aminocyclopropane-1-carboxylic acid (ACC) in jai1-1 and a premature pollen release from stamens, a phenotype similarly visible in an ethylene overproducing mutant. Application of jasmonates to flowers of transgenic plants affected in jasmonate biosynthesis diminished expression of ethylene-related genes, whereas the double mutant jai1-1 NeverRipe (ethylene insensitive) showed a complementation of jai1-1 phenotype in terms of dehiscence and pollen release.
Our data suggest an essential role of jasmonates in the temporal inhibition of ethylene production to prevent premature desiccation of stamens and to ensure proper timing in flower development.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-015-0135-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4443647  PMID: 25895675
Array hybridization; Desiccation; Ethylene; Flower development; Jasmonic acid; Jasmonic acid-insensitive; Metabolite profiling; Pollen development
47.  Long-range regulatory interactions at the 4q25 atrial fibrillation risk locus involve PITX2c and ENPEP 
BMC Biology  2015;13:26.
Recent genome-wide association studies have uncovered genomic loci that underlie an increased risk for atrial fibrillation, the major cardiac arrhythmia in humans. The most significant locus is located in a gene desert at 4q25, approximately 170 kilobases upstream of PITX2, which codes for a transcription factor involved in embryonic left-right asymmetry and cardiac development. However, how this genomic region functionally and structurally relates to PITX2 and atrial fibrillation is unknown.
To characterise its function, we tested genomic fragments from 4q25 for transcriptional activity in a mouse atrial cardiomyocyte cell line and in transgenic mouse embryos, identifying a non-tissue-specific potentiator regulatory element. Chromosome conformation capture revealed that this region physically interacts with the promoter of the cardiac specific isoform of Pitx2. Surprisingly, this regulatory region also interacts with the promoter of the next neighbouring gene, Enpep, which we show to be expressed in regions of the developing mouse heart essential for cardiac electrical activity.
Our data suggest that de-regulation of both PITX2 and ENPEP could contribute to an increased risk of atrial fibrillation in carriers of disease-associated variants, and show the challenges that we face in the functional analysis of genome-wide disease associations.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-015-0138-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4416339  PMID: 25888893
Atrial fibrillation; Chromosome conformation; ENPEP; PITX2; Regulatory element
48.  Molecular basis of sugar recognition by collectin-K1 and the effects of mutations associated with 3MC syndrome 
BMC Biology  2015;13:27.
Collectin-K1 (CL-K1, or CL-11) is a multifunctional Ca2+-dependent lectin with roles in innate immunity, apoptosis and embryogenesis. It binds to carbohydrates on pathogens to activate the lectin pathway of complement and together with its associated serine protease MASP-3 serves as a guidance cue for neural crest development. High serum levels are associated with disseminated intravascular coagulation, where spontaneous clotting can lead to multiple organ failure. Autosomal mutations in the CL-K1 or MASP-3 genes cause a developmental disorder called 3MC (Carnevale, Mingarelli, Malpuech and Michels) syndrome, characterised by facial, genital, renal and limb abnormalities. One of these mutations (Gly204Ser in the CL-K1 gene) is associated with undetectable levels of protein in the serum of affected individuals.
In this study, we show that CL-K1 primarily targets a subset of high-mannose oligosaccharides present on both self- and non-self structures, and provide the structural basis for its ligand specificity. We also demonstrate that three disease-associated mutations prevent secretion of CL-K1 from mammalian cells, accounting for the protein deficiency observed in patients. Interestingly, none of the mutations prevent folding or oligomerization of recombinant fragments containing the mutations in vitro. Instead, they prevent Ca2+ binding by the carbohydrate-recognition domains of CL-K1. We propose that failure to bind Ca2+ during biosynthesis leads to structural defects that prevent secretion of CL-K1, thus providing a molecular explanation of the genetic disorder.
We have established the sugar specificity of CL-K1 and demonstrated that it targets high-mannose oligosaccharides on self- and non-self structures via an extended binding site which recognises the terminal two mannose residues of the carbohydrate ligand. We have also shown that mutations associated with a rare developmental disorder called 3MC syndrome prevent the secretion of CL-K1, probably as a result of structural defects caused by disruption of Ca2+ binding during biosynthesis.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-015-0136-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4431178  PMID: 25912189
Complement activation; structural biology; C-type lectin; 3MC syndrome
49.  Gene-specific selective sweeps in bacteria and archaea caused by negative frequency-dependent selection 
BMC Biology  2015;13:20.
Fixation of beneficial genes in bacteria and archaea (collectively, prokaryotes) is often believed to erase pre-existing genomic diversity through the hitchhiking effect, a phenomenon known as genome-wide selective sweep. Recent studies, however, indicate that beneficial genes spread through a prokaryotic population via recombination without causing genome-wide selective sweeps. These gene-specific selective sweeps seem to be at odds with the existing estimates of recombination rates in prokaryotes, which appear far too low to explain such phenomena.
We use mathematical modeling to investigate potential solutions to this apparent paradox. Most microbes in nature evolve in heterogeneous, dynamic communities, in which ecological interactions can substantially impact evolution. Here, we focus on the effect of negative frequency-dependent selection (NFDS) such as caused by viral predation (kill-the-winner dynamics). The NFDS maintains multiple genotypes within a population, so that a gene beneficial to every individual would have to spread via recombination, hence a gene-specific selective sweep. However, gene loci affected by NFDS often are located in variable regions of microbial genomes that contain genes involved in the mobility of selfish genetic elements, such as integrases or transposases. Thus, the NFDS-affected loci are likely to experience elevated rates of recombination compared with the other loci. Consequently, these loci might be effectively unlinked from the rest of the genome, so that NFDS would be unable to prevent genome-wide selective sweeps. To address this problem, we analyzed population genetic models of selective sweeps in prokaryotes under NFDS. The results indicate that NFDS can cause gene-specific selective sweeps despite the effect of locally elevated recombination rates, provided NFDS affects more than one locus and the basal rate of recombination is sufficiently low. Although these conditions might seem to contradict the intuition that gene-specific selective sweeps require high recombination rates, they actually decrease the effective rate of recombination at loci affected by NFDS relative to the per-locus basal level, so that NFDS can cause gene-specific selective sweeps.
Because many free-living prokaryotes are likely to evolve under NFDS caused by ubiquitous viruses, gene-specific selective sweeps driven by NFDS are expected to be a major, general phenomenon in prokaryotic populations.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-015-0131-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4410459  PMID: 25928466
50.  snoRNAs are a novel class of biologically relevant Myc targets 
BMC Biology  2015;13:25.
Myc proteins are essential regulators of animal growth during normal development, and their deregulation is one of the main driving factors of human malignancies. They function as transcription factors that (in vertebrates) control many growth- and proliferation-associated genes, and in some contexts contribute to global gene regulation.
We combine chromatin immunoprecipitation-sequencing (ChIPseq) and RNAseq approaches in Drosophila tissue culture cells to identify a core set of less than 500 Myc target genes, whose salient function resides in the control of ribosome biogenesis. Among these genes we find the non-coding snoRNA genes as a large novel class of Myc targets. All assayed snoRNAs are affected by Myc, and many of them are subject to direct transcriptional activation by Myc, both in Drosophila and in vertebrates. The loss of snoRNAs impairs growth during normal development, whereas their overexpression increases tumor mass in a model for neuronal tumors.
This work shows that Myc acts as a master regulator of snoRNP biogenesis. In addition, in combination with recent observations of snoRNA involvement in human cancer, it raises the possibility that Myc’s transforming effects are partially mediated by this class of non-coding transcripts.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-015-0132-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4430873  PMID: 25888729
Myc; Transcription; snoRNA; Ribosome; Growth; Drosophila

Results 26-50 (959)