Ageing-associated changes in transcriptional elongation influence longevity

Physiological homeostasis becomes compromised during ageing, as a result of impairment of cellular processes, including transcription and RNA splicing1-4. However, the molecular mechanisms leading to the loss of transcriptional fidelity are so far elusive, as are ways of preventing it. Here we profiled and analysed genome-wide, ageing-related changes in transcriptional processes across different organisms: nematodes, fruitflies, mice, rats and humans. The average transcriptional elongation speed (RNA polymerase II speed) increased with age in all five species. Along with these changes in elongation speed, we observed changes in splicing, including a reduction of unspliced transcripts and the formation of more circular RNAs. Two lifespan-extending interventions, dietary restriction and lowered insulin-IGF signalling, both reversed most of these ageing-related changes. Genetic variants in RNA polymerase II that reduced its speed in worms5 and flies6 increased their lifespan. Similarly, reducing the speed of RNA polymerase II by overexpressing histone components, to counter age-associated changes in nucleosome positioning, also extended lifespan in flies and the division potential of human cells. Our findings uncover fundamental molecular mechanisms underlying animal ageing and lifespan-extending interventions, and point to possible preventive measures

Taxonomy of the family Arenaviridae and the order Bunyavirales : update 2018

In 2018, the family Arenaviridae was expanded by inclusion of 1 new genus and 5 novel species. At the same time, the recently established order Bunyavirales was expanded by 3 species. This article presents the updated taxonomy of the family Arenaviridae and the order Bunyavirales as now accepted by the International Committee on Taxonomy of Viruses (ICTV) and summarizes additional taxonomic proposals that may affect the order in the near future.Peer reviewe

Transcription as a force partitioning the eukaryotic genome

Eukaryotic genomes - until recently dealt with as if they were a cohort of linear DNA molecules - are perplexed three-dimensional structures, the exact conformation of which profoundly affects genome function. Recent advances in molecular biology and DNA sequencing technologies have led to a new understanding of the folding of chromatin in the nucleus. Changes in chromatin structure underlie deployment of new gene expression programs during development, differentiation, or disease. In this review, we revisit data pointing to, arguably, the major force that shapes genomes: transcription of DNA into RNA

Mosquito community composition shapes virus prevalence patterns along anthropogenic disturbance gradients

Previously unknown pathogens often emerge from primary ecosystems, but there is little knowledge on the mechanism behind. Most studies analyzing the influence of land-use change on pathogen emergence focus on a single host-pathogen system and often observe contrary effects. We studied virus diversity and prevalence patterns in natural and disturbed ecosystems using a multi-host and multi-taxa approach. We detected 331 viral sequences pertaining to 49 viruses of ten RNA-virus families. Highest host and virus diversity was observed in pristine and intermediately disturbed habitats. The majority of the viruses was detected with low prevalence. However, nine viruses were found frequently of which five viruses increased in prevalence from pristine to disturbed habitats, in congruence with the dilution effect hypothesis. Interestingly, the observed increased prevalence of these five viruses in disturbed habitats was not caused by higher host infection rates but by increased host abundance, an effect tentatively named abundance effect

On TESOL \u2776: Selections based on teaching done at the Tenth Annual TESOL Convention [in New York, NY March 2-7, 1976]

Anne Campbell-Johnson (with R. Axelrod, L. Lugo and P. Zirkel) is a contributing author, Native language and black dialect interference in the oral reproduction of standard English by Puerto Rican pupils , pp. 129-135. Book description: The purposes of this study are stated to be twofold: (1) to determine the relative effects of the native language and black dialect influences on the oral English performance of Puerto Rican pupils in mainland schools and (2) to assess the relationship of these sources of linguistic interference with aural ability in English, reading ability in English, and time in mainland schools. The oral repetition technique is used with 80 Puerto Rican children enrolled in grades 2-4 in a predominantly Puerto Rican bilingual school. Findings indicate a significant positive correlation between degrees of black dialect interference and time in mainland schools. Significant inverse correlations are indicated between degree of black dialect interference and reading ability in English and between degree of Spanish interference and aural ability in English. Time in mainland schools is said to be significantly related to aural ability in English but not to reading ability. A relationship approaching significance between the degree of native language interference and reading ability in English is considered to indicate a need to explore more systematic approaches to the teaching of English to Spanish speaking students

Detection of Two Highly Diverse Peribunyaviruses in Mosquitoes from Palenque, Mexico

The Peribunyaviridae family contains the genera Orthobunyavirus, Herbevirus, Pacuvirus, and Shangavirus. Orthobunyaviruses and pacuviruses are mainly transmitted by blood-feeding insects and infect a variety of vertebrates whereas herbeviruses and shangaviruses have a host range restricted to insects. Here, we tested mosquitoes from a tropical rainforest in Mexico for infections with peribunyaviruses. We identified and characterized two previously unknown viruses, designated Baakal virus (BKAV) and Lakamha virus (LAKV). Sequencing and de novo assembly of the entire BKAV and LAKV genomes revealed that BKAV is an orthobunyavirus and LAKV is likely to belong to a new genus. LAKV was almost equidistant to the established peribunyavirus genera and branched as a deep rooting solitary lineage basal to herbeviruses. Virus isolation attempts of LAKV failed. BKAV is most closely related to the bird-associated orthobunyaviruses Koongol virus and Gamboa virus. BKAV was successfully isolated in mosquito cells but did not replicate in common mammalian cells from various species and organs. Also cells derived from chicken were not susceptible. Interestingly, BKAV can infect cells derived from a duck species that is endemic in the region where the BKAV-positive mosquito was collected. These results suggest a narrow host specificity and maintenance in a mosquito-bird transmission cycle

TNFα signalling primes chromatin for NF-κB binding and induces rapid and widespread nucleosome repositioning

Background The rearrangement of nucleosomes along the DNA fiber profoundly affects gene expression, but little is known about how signalling reshapes the chromatin landscape, in three-dimensional space and over time, to allow establishment of new transcriptional programs. Results Using micrococcal nuclease treatment and high-throughput sequencing, we map genome-wide changes in nucleosome positioning in primary human endothelial cells stimulated with tumour necrosis factor alpha (TNFα) - a proinflammatory cytokine that signals through nuclear factor kappa-B (NF-κB). Within 10 min, nucleosomes reposition at regions both proximal and distal to NF-κB binding sites, before the transcription factor quantitatively binds thereon. Similarly, in long TNFα-responsive genes, repositioning precedes transcription by pioneering elongating polymerases and appears to nucleate from intragenic enhancer clusters resembling super-enhancers. By 30 min, widespread repositioning throughout megabase pair-long chromosomal segments, with consequential effects on three-dimensional structure (detected using chromosome conformation capture), is seen. Conclusions Whilst nucleosome repositioning is viewed as a local phenomenon, our results point to effects occurring over multiple scales. Here, we present data in support of a TNFα-induced priming mechanism, mostly independent of NF-κB binding and/or elongating RNA polymerases, leading to a plastic network of interactions that affects DNA accessibility over large domains

Redundant and specific roles of cohesin STAG subunits in chromatin looping and transcriptional control

Cohesin is a ring-shaped multiprotein complex that is crucial for 3D genome organization and transcriptional regulation during differentiation and development. It also confers sister chromatid cohesion and facilitates DNA damage repair. Besides its core subunits SMC3, SMC1A, and RAD21, cohesin in somatic cells contains one of two orthologous STAG subunits, STAG1 or STAG2. How these variable subunits affect the function of the cohesin complex is still unclear. STAG1- and STAG2-cohesin were initially proposed to organize cohesion at telomeres and centromeres, respectively. Here, we uncover redundant and specific roles of STAG1 and STAG2 in gene regulation and chromatin looping using HCT116 cells with an auxin-inducible degron (AID) tag fused to either STAG1 or STAG2. Following rapid depletion of either subunit, we perform high-resolution Hi-C, gene expression, and sequential ChIP studies to show that STAG1 and STAG2 do not co-occupy individual binding sites and have distinct ways by which they affect looping and gene expression. These findings are further supported by single-molecule localizations via direct stochastic optical reconstruction microscopy (dSTORM) super-resolution imaging. Since somatic and congenital mutations of the STAG subunits are associated with cancer (STAG2) and intellectual disability syndromes with congenital abnormalities (STAG1 and STAG2), we verified STAG1-/STAG2-dependencies using human neural stem cells, hence highlighting their importance in particular disease contexts

Binding of nuclear factor kappa B to noncanonical consensus sites reveals its multimodal role during the early inflammatory response

Mammalian cells have developed intricate mechanisms to interpret, integrate, and respond to extracellular stimuli. For example, tumor necrosis factor (TNF) rapidly activates proinflammatory genes, but our understanding of how this occurs against the ongoing transcriptional program of the cell is far from complete. Here, we monitor the early phase of this cascade at high spatiotemporal resolution in TNF-stimulated human endothelial cells. NF-kappa B, the transcription factor complex driving the response, interferes with the regulatory machinery by binding active enhancers already in interaction with gene promoters. Notably, >50% of these enhancers do not encode canonical NF-kappa B binding motifs. Using a combination of genomics tools, we find that binding site selection plays a key role in NF-kappa B-mediated transcriptional activation and repression. We demonstrate the latter by describing the synergy between NF-kappa B and the corepressor JDP2. Finally, detailed analysis of a 2.8-Mbp locus using sub-kbp-resolution targeted chromatin conformation capture and genome editing uncovers how NF-kappa B that has just entered the nucleus exploits pre-existing chromatin looping to exert its multimodal role. This work highlights the involvement of topology in cis-regulatory element function during acute transcriptional responses, where primary DNA sequence and its higher-order structure constitute a regulatory context leading to either gene activation or repression