Pseudogap opening in the two-dimensional Hubbard model: A functional renormalization group analysis

Using the recently introduced multiloop extension of the functional renormalization group, we compute the frequency- and momentum-dependent self-energy of the two-dimensional Hubbard model at half filling and weak coupling. We show that, in the truncated-unity approach for the vertex, it is essential to adopt the Schwinger-Dyson form of the self-energy flow equation in order to capture the pseudogap opening. We provide an analytic understanding of the key role played by the flow scheme in correctly accounting for the impact of the antiferromagnetic fluctuations. For the resulting pseudogap, we present a detailed numerical analysis of its evolution with temperature, interaction strength, and loop order.Comment: 15 pages, 15 figures, version as publishe

Extension of imprinted silencing in the Igf2r cluster in extra-embryonic tissues

Geprägte Gene kommen in Gruppen vor, welche meist von einer makro-nichtprotein- kodierende (mnk) RNA reguliert werden. Die inneren Gene der Gruppe können von der mnk RNA überlappt werden und zeigen im gesamten Embryo und in extra-embryonalen Geweben geprägte Expression. Die äußeren Gene der Gruppe werden nicht von der mnk RNA überlappt und zeigen nur in extra-embryonalen Geweben eine geprägte Expression. Extraembryonales Gewebe besteht aus unterschiedlichen Zelltypen und kann von mütterlichem Gewebe kontaminiert werden. Dadurch kann die genomische Prägung des untersuchten Gens durch biallelische Expression im kontaminierenden Gewebe maskiert werden. Um Kontaminationen zu vermeiden, haben wir eine effiziente Methode entwickelt, um eine pure Population von viszeralem Endoderm (VE) aus dem Dottersack zu isolieren. VE ist somit eine gutes extra-embryonales Model- Gewebe um neue geprägte Gene zu finden. Die monoallelische “T-hairpin” Deletion, welche die gut charakterisierte geprägte Igf2r Gengruppe einschließt, wird genutzt um im VE nach neuen geprägten Genen zu suchen. In der Igf2r Gengruppe reguliert die mnk RNA Airn die Expression der geprägten Gene. Um zu testen, ob ein geprägtes Gen zu der Igf2r Gengruppe gehört, habe ich untersucht ob dieses von Airn reguliert wird. Dabei habe ich Wildtyp Embryonen mit Embryonen verglichen, welche eine gekürzte, nicht funktionelle Variante von Airn exprimieren. Mit diesem Ansatz habe ich 15 Gene getestet, wovon drei vorranging vom mütterlichen Allele exprimiert werden. Zusätzlich zeigen meine vorläufigen Daten, dass das in der Plazenta mütterliche geprägte Gen Pde10a von Airn reguliert wird. Zusammenfassend zeigen meine Ergebnisse, dass die Igf2r Gruppe nicht wie bisher angenommen 440Kb groß ist, sondern sich in extra-embryonalen Gewebe auf bis zu 4Mb ausbreitet.Imprinted genes occur in clusters, several of which are regulated by a macro long non-protein-coding (lnc) RNA. Inner genes within the cluster can be overlapped by the macro lncRNA and show multi-lineage (ML) imprinted expression in the embryo and extra-embryonic tissues, while outer genes are not overlapped by the macro lncRNA and show extra-embryonic-lineage (EXEL) specific imprinted expression. Extra-embryonic tissues are a mixture of ML and EXEL cell types, so imprinted expression may be masked by biallelic expression in ML tissues if a whole organ is examined. We have developed an efficient method to isolate a pure population of visceral endoderm (VE), an EXEL cell type, providing a system to discover new imprinted genes as EXEL tissues show imprinted expression of both, ML and EXEL genes, and masking is avoided. Using this system I have taken advantage of the T-hairpin uniparental deletion to systematically check for the limits of the well-characterised Igf2r cluster. Imprinted genes can be definitively shown to be part of these Igf2r cluster by determining if they are regulated by the Airn macro lncRNA. This is done by comparing wildtype embryos with those containing a truncated and non-functional Airn. Using this system I have tested 15 genes and identified three genes showing biased imprinted expression in VE and shown that they are part of the Igf2r cluster. In addition, I have preliminary data confirming a recent report that Pde10a shows imprinted expression in placenta, and have shown that imprinted silencing is regulated by Airn. Taken together these results extend the known region showing imprinted expression in the Igf2r cluster from 440Kb up to 4Mb in extra-embryonic tissues

Interaction flow method for many-fermion systems

We propose an interaction flow scheme that sums up the perturbation expansion of many-particle systems by successively increasing the interaction strength. It combines the unbiasedness of renormalization group methods with the simplicity of straight-forward perturbation theory. Applying the scheme to fermions in one dimension and to the two-dimensional Hubbard model we find that at one-loop level and low temperatures there is ample agreement with previous one-loop renormalization group approaches. We furthermore present results for the momentum-dependence of spin, charge and pairing interactions in the two-dimensional Hubbard model.Comment: 14 pages, 14 figure

Diverse epigenetic mechanisms maintain parental imprints within the embryonic and extraembryonic lineages

Genomic imprinting and X chromosome inactivation (XCI) require epigenetic mechanisms to encode allele-specific expression, but how these specific tasks are accomplished at single loci or across chromosomal scales remains incompletely understood. Here, we systematically disrupt essential epigenetic pathways within polymorphic embryos in order to examine canonical and non-canonical genomic imprinting as well as XCI. We find that DNA methylation and Polycomb group repressors are indispensable for autosomal imprinting, albeit at distinct gene sets. Moreover, the extraembryonic ectoderm relies on a broader spectrum of imprinting mechanisms, including non-canonical targeting of maternal endogenous retrovirus (ERV)-driven promoters by the H3K9 methyltransferase G9a. We further identify Polycomb-dependent and -independent gene clusters on the imprinted X chromosome, which appear to reflect distinct domains of Xist-mediated suppression. From our data, we assemble a comprehensive inventory of the epigenetic pathways that maintain parent-specific imprinting in eutherian mammals, including an expanded view of the placental lineage

Allelome.PRO, a pipeline to define allele-specific genomic features from high-throughput sequencing data

Detecting allelic biases from high-throughput sequencing data requires an approach that maximises sensitivity while minimizing false positives. Here, we present Allelome.PRO, an automated user-friendly bioinformatics pipeline, which uses high-throughput sequencing data from reciprocal crosses of two genetically distinct mouse strains to detect allele-specific expression and chromatin modifications. Allelome.PRO extends approaches used in previous studies that exclusively analyzed imprinted expression to give a complete picture of the ‘allelome’ by automatically categorising the allelic expression of all genes in a given cell type into imprinted, strain-biased, biallelic or non-informative. Allelome.PRO offers increased sensitivity to analyze lowly expressed transcripts, together with a robust false discovery rate empirically calculated from variation in the sequencing data. We used RNA-seq data from mouse embryonic fibroblasts from F1 reciprocal crosses to determine a biologically relevant allelic ratio cutoff, and define for the first time an entire allelome. Furthermore, we show that Allelome.PRO detects differential enrichment of H3K4me3 over promoters from ChIP-seq data validating the RNA-seq results. This approach can be easily extended to analyze histone marks of active enhancers, or transcription factor binding sites and therefore provides a powerful tool to identify candidate cis regulatory elements genome wide

Cis and trans effects differentially contribute to the evolution of promoters and enhancers

Background Gene expression differences between species are driven by both cis and trans effects. Whereas cis effects are caused by genetic variants located on the same DNA molecule as the target gene, trans effects are due to genetic variants that affect diffusible elements. Previous studies have mostly assessed the impact of cis and trans effects at the gene level. However, how cis and trans effects differentially impact regulatory elements such as enhancers and promoters remains poorly understood. Here, we use massively parallel reporter assays to directly measure the transcriptional outputs of thousands of individual regulatory elements in embryonic stem cells and measure cis and trans effects between human and mouse. Results Our approach reveals that cis effects are widespread across transcribed regulatory elements, and the strongest cis effects are associated with the disruption of motifs recognized by strong transcriptional activators. Conversely, we find that trans effects are rare but stronger in enhancers than promoters and are associated with a subset of transcription factors that are differentially expressed between human and mouse. While we find that cis-trans compensation is common within promoters, we do not see evidence of widespread cis-trans compensation at enhancers. Cis-trans compensation is inversely correlated with enhancer redundancy, suggesting that such compensation may often occur across multiple enhancers. Conclusions Our results highlight differences in the mode of evolution between promoters and enhancers in complex mammalian genomes and indicate that studying the evolution of individual regulatory elements is pivotal to understand the tempo and mode of gene expression evolution.K.M. was a National Science Foundation Graduate Research Fellow under grant no. DGE1144152 during the majority of the project. M.M. was a Gilead Fellow of the Life Sciences Research Foundation during part of the project and is currently supported by the Spanish Ministry of Science and Innovation with a Ramon y Cajal grant (RYC-2017-22249). J.L.R. is an HHMI faculty scholar.Peer ReviewedPostprint (published version

The Airn lncRNA does not require any DNA elements within its locus to silence distant imprinted genes

Long non-coding (lnc) RNAs are numerous and found throughout the mammalian genome, and many are thought to be involved in the regulation of gene expression. However, the majority remain relatively uncharacterised and of uncertain function making the use of model systems to uncover their mode of action valuable. Imprinted lncRNAs target and recruit epigenetic silencing factors to a cluster of imprinted genes on the same chromosome, making them one of the best characterized lncRNAs for silencing distant genes in cis. In this study we examined silencing of the distant imprinted gene Slc22a3 by the lncRNA Airn in the Igf2r imprinted cluster in mouse. Previously we proposed that imprinted lncRNAs may silence distant imprinted genes by disrupting promoter-enhancer interactions by being transcribed through the enhancer, which we called the enhancer interference hypothesis. Here we tested this hypothesis by first using allele-specific chromosome conformation capture (3C) to detect interactions between the Slc22a3 promoter and the locus of the Airn lncRNA that silences it on the paternal chromosome. In agreement with the model, we found interactions enriched on the maternal allele across the entire Airn gene consistent with multiple enhancer-promoter interactions. Therefore, to test the enhancer interference hypothesis we devised an approach to delete the entire Airn gene. However, the deletion showed that there are no essential enhancers for Slc22a2, Pde10a and Slc22a3 within the Airn gene, strongly indicating that the Airn RNA rather than its transcription is responsible for silencing distant imprinted genes. Furthermore, we found that silent imprinted genes were covered with large blocks of H3K27me3 on the repressed paternal allele. Therefore we propose an alternative hypothesis whereby the chromosome interactions may initially guide the lncRNA to target imprinted promoters and recruit repressive chromatin, and that these interactions are lost once silencing is established

Mapping the mouse Allelome reveals tissue-specific regulation

In Säugetieren können genetische und epigenetische Unterschiede zwischen den elterlichen Allelen zu allele-spezifischer Genexpression (AGE) führen. RNA-seq wurde seit der Entwicklung von Hochdurchsatzsequenzierung verwendet um AGE in Mensch- und Mausgeweben zu detektieren. Da man die DNA-Sequenz der Eltern benötigt, erweist sich ein genomweiter Nachweis von allele-spezifischer Genexpression im Menschen als schwierig. Ein geeigneteres Modell um AGE nachzuweisen stellen Kreuzungen von genetisch unterschiedlichen Stämmen von Labormäuse dar, da die genetischen Unterschiede zwischen vielen Stämmen bereits bekannt sind. Obwohl AGE Detektion mittels RNA-seq eine anerkannte Methode ist, gab es zu Beginn dieser Studie keine bioinformatische Software, die präzise und mit einer niedrigen Fehlerquote, AGE detektiert. Deshalb entwickelten wir im ersten Teil dieser Studie die benutzerfreundliche Software Allelome.PRO, welche mit hoher Präzision allele-spezifische Genexpression oder Histonmodifikationen erfasst. Zusätzlich klassifiziert die Software jedes Gen in einem Zelltyp in eine der folgenden Kategorien: biallelisch, Mausstamm-spezifisch, geprägt oder nicht-informativ. Dadurch wird das gesamte allele-spezifische Bild aller aktiven Gene – „Allelome“ genannt - abgebildet. Im nächsten Schritt verwendeten wir Allelome.PRO um AGE für Protein und nicht-Protein-kodierenden (nk) Gene in 23 Geweben, in jeweils verschiedenen Entwicklungsstadien der Maus, zu identifizieren um das Maus Allelome zu erhalten. Diese Entwicklungsstadien beinhalten pluripotente, embryonale, extra-embryonale, neugeborene und adulte Gewebe. Diese an der Maus neuartige Analyse führte zu folgenden drei Erkenntnissen. Erstens wurden viele Gene mit gewebespezifischer Mausstamm-spezifischer Expression identifiziert und dass dieses Expressionsmuster von naheliegenden Mausstamm-spezifischen Expressions-Aktivatoren reguliert wird. Diese Aktivatoren werden von Histonen mit der H3K27ac Modifikation markiert. Zweitens wurden in 19 weiblichen Geweben eine unerwartet große Zahl an Genen, die dem Prozess der X-Chromosom-Inaktivierung entkommen, genannt „Escaper“, gefunden. Im Gegensatz zu den meisten Studien, die von niedrigen Escaper-Prozenten in der Maus berichten, fanden wir einen dem Menschen ähnlichen Prozentsatz von 15 Prozent. Bemerkenswert ist der hohe Escaper-Anteil von 50 Prozent im adulten Beinmuskel. Drittens konnten wir zeigen das geprägte Gengruppen viel größer sind als bisher angenommen und die Größe dramatisch zwischen Geweben und Entwicklungsstadien variiert. Insbesondere zeigen wir anhand von genetischen Mausmodellen, dass sich die geprägte Igf2r Gengruppe in der Plazenta über zehn Megabasen erstreckt und somit die größte, geprägte Region in der Maus repräsentiert. Zusammenfassend zeigen unsere Ergebnisse, dass AGE welche durch genetische Unterschiede zwischen den Allelen oder durch epigenetische Prozesse, wie X-Chromosom-Inaktivierung oder genomischer Prägung entstehen, überraschend oft gewebespezifisch ist.In mammals, genetic or epigenetic differences between the parental alleles can results in allele-specific expression. Since the development of high-throughput sequencing, RNA-seq has been used to detect allele-specific expression in human and mouse tissues. Genome-wide detection of allelic expression in human is difficult since it requires genotyping of the parents to distinguish the alleles. In contrast the inbred mouse model is a powerful system to map allele-specific expression since the genetic differences between different laboratory strains are known. Although RNA-seq is a powerful tool, a bioinformatics pipeline with increased sensitivity and low levels of false positive calls was lacking. Here we developed Allelome.PRO, a user-friendly, fully automated bioinformatics pipeline, which robustly detects allele-specific expression or chromatin modification from high-throughput sequencing data. The pipeline automatically characterizes the allelic profile from all genes in one cell type into biallelic, strain-biased, imprinted or non-informative and thus provides the full allelic expression picture, “the Allelome”. Next we used the pipeline to generate the most comprehensive survey of allelic expression for protein and non-coding genes yet known, by conducting RNA-seq on 23 mouse tissues throughout the development, including pluripotent, embryonic, extra-embryonic, neonatal and adult tissues, to map for the first time “the mouse Allelome”. The mouse Allelome reveals that tissue-specific strain-biased expression is correlated with nearby strain-biased H3K27ac enrichment, implying regulation by tissue-specific allelic enhancers. Next we mapped X-chromosome inactivation (XCI) escaper genes in 19 female tissues. In contrast to most previous reports in mouse that reported lower numbers, we found an average of 15% escapers per tissue similar to human, with the notable exception of adult leg muscle that showed 50% escaper genes. In addition we show that imprinted clusters are much larger than previously known, and change their size dramatically among tissues and during development. In particular we genetically demonstrate here that the Igf2r cluster extends over 10Mb in placenta, representing the largest imprinted region in mouse. In summary we find that allelic expression arising from genetic differences between the alleles or from epigenetic processes such as XCI and genomic imprinting, is surprisingly highly tissue-specific

Absolute and relative reliability of acute effects of aerobic exercise on executive function in seniors

Aging is accompanied by a decline of executive function. Aerobic exercise training induces moderate improvements of cognitive domains (i.e., attention, processing, executive function, memory) in seniors. Most conclusive data are obtained from studies with dementia or cognitive impairment. Confident detection of exercise training effects requires adequate between-day reliability and low day-to-day variability obtained from acute studies, respectively. These absolute and relative reliability measures have not yet been examined for a single aerobic training session in seniors.; Twenty-two healthy and physically active seniors (age: 69 ± 3 y, BMI: 24.8 ± 2.2, VO2peak: 32 ± 6 mL/kg/bodyweight) were enrolled in this randomized controlled cross-over study. A repeated between-day comparison [i.e., day 1 (habituation) vs. day 2 & day 2 vs. day 3] of executive function testing (Eriksen-Flanker-Test, Stroop-Color-Test, Digit-Span, Five-Point-Test) before and after aerobic cycling exercise at 70% of the heart rate reserve [0.7 × (HRmax - HRrest)] was conducted. Reliability measures were calculated for pre, post and change scores.; Large between-day differences between day 1 and 2 were found for reaction times (Flanker- and Stroop Color testing) and completed figures (Five-Point test) at pre and post testing (0.002 < p < 0.05, 0.16 < ɳp(2) < 0.38). These differences notably declined when comparing day 2 and 3. Absolute between days variability (CoV) dropped from 10 to 5% when comparing day 2 vs. day 3 instead of day 1 vs. day 2. Also ICC ranges increased from day 1 vs. day 2 (0.65 < ICC < 0.87) to day 2 vs. day 3 (0.40 < ICC < 0.93). Interestingly, reliability measures for pre-post change scores were low (0.02 < ICC < 0.71). These data did not improve when comparing day 2 with day 3. During inhibition tests, reaction times showed excellent reliability values compared to the poor to fair reliability of accuracy.; Notable habituation to the whole testing procedure should be considered as it increased the reliability of different executive function tests. Change scores of executive function after acute aerobic exercise cannot be detected reliably. Large intra- and inter-individual of responses to acute aerobic exercise in seniors can be presumed