Basis of gene-specific transcription regulation by the Integrator complex.

The Integrator complex attenuates gene expression via the premature termination of RNA polymerase II (RNAP2) at promoter-proximal pausing sites. It is required for stimulus response, cell differentiation, and neurodevelopment, but how gene-specific and adaptive regulation by Integrator is achieved remains unclear. Here, we identify two sites on human Integrator subunits 13/14 that serve as binding hubs for sequence-specific transcription factors (TFs) and other transcription effector complexes. When Integrator is attached to paused RNAP2, these hubs are positioned upstream of the transcription bubble, consistent with simultaneous TF-promoter tethering. The TFs co-localize with Integrator genome-wide, increase Integrator abundance on target genes, and co-regulate responsive transcriptional programs. For instance, sensory cilia formation induced by glucose starvation depends on Integrator-TF contacts. Our data suggest TF-mediated promoter recruitment of Integrator as a widespread mechanism for targeted transcription regulation.

GRaNIE and GRaNPA: inference and evaluation of enhancer-mediated gene regulatory networks.

Enhancers play a vital role in gene regulation and are critical in mediating the impact of noncoding genetic variants associated with complex traits. Enhancer activity is a cell-type-specific process regulated by transcription factors (TFs), epigenetic mechanisms and genetic variants. Despite the strong mechanistic link between TFs and enhancers, we currently lack a framework for jointly analysing them in cell-type-specific gene regulatory networks (GRN). Equally important, we lack an unbiased way of assessing the biological significance of inferred GRNs since no complete ground truth exists. To address these gaps, we present GRaNIE (Gene Regulatory Network Inference including Enhancers) and GRaNPA (Gene Regulatory Network Performance Analysis). GRaNIE (https://git.embl.de/grp-zaugg/GRaNIE) builds enhancer-mediated GRNs based on covariation of chromatin accessibility and RNA-seq across samples (e.g. individuals), while GRaNPA (https://git.embl.de/grp-zaugg/GRaNPA) assesses the performance of GRNs for predicting cell-type-specific differential expression. We demonstrate their power by investigating gene regulatory mechanisms underlying the response of macrophages to infection, cancer and common genetic traits including autoimmune diseases. Finally, our methods identify the TF PURA as a putative regulator of pro-inflammatory macrophage polarisation.

SARS-CoV-2 historical global testing and genomic variability.

The world has been dealing with the SARS-COV-2 pandemic since December 2019 and a lot of effort has focused on tracking the spread of the virus by gathering information regarding testing statistics and generating viral genomic sequences. Unfortunately, there is neither a single comprehensive resource with global historical testing data nor a centralized database with summary statistics of the identified genomic variants. We merged different pre-aggregated historical testing data and complemented them with our manually extracted ones, which consist of 6852 historical test statistics from 76 countries/states unreported in any other dataset, at the date of submission, making our dataset the most comprehensive to date. We also analyzed all publicly deposited SARS-CoV-2 genomic sequences in GISAID and annotated their variants. Both datasets can be accessed through our interactive dashboard which also provides important insights on different outbreak trends across countries and states. The dashboard is available at https://bioinfo.lau.edu.lb/gkhazen/covid19 . A daily updated version of the datasets can be downloaded from github.com/KhazenLab/covid19-data.

Identification of transmission chains and clusters associated with COVID-19 in Tunisia.

BACKGROUND: The aim of this study was to characterize the transmission chains and clusters of COVID-19 infection in Tunisia. METHODS: All cases were confirmed by Reverse Transcriptase Polymerase Chain Reaction of a nasopharyngeal specimen. Contact tracing is undertaken for all confirmed cases in order to identify close contacts that will be systematically screened and quarantined. Transmission chains were identified based on field investigation, contact tracing, results of screening tests and by assessing all probable mode of transmission and interactions. RESULTS: As of May 18, 2020, 656 cases out of a total of 1043 confirmed cases of Coronavirus disease 2019 belong to 127 transmission chains identified during the epidemic (mean age 42.36 years, Standard deviation 19.56 and sex ratio 0.86). The virus transmission is the most concentrated in the governorate of Tunis (31.5%), Ariana (10.2%) and Ben Arous (10.2%). Virus transmission occurred 50 times (9.72% of secondary transmission events) between two different governorates. A maximum of seven generations of secondary infection was identified, whereas 62% of these secondary infections belong the first generation. A total of 11 "super spreader" cases were identified in this investigation. Four large clusters have been identified. The evolution of secondary cases highlighted two peaks: one in 2nd April and a second in 16 th April whereas imported cases caused local transmission of virus during the early phase of the epidemic. CONCLUSION: Correct contact tracing and early active case finding is useful to identify transmission chains and source of infection in order to contain the widespread transmission in the community.

Expanded genome-wide comparisons give novel insights into population structure and genetic heterogeneity of Leishmania tropica complex.

Leishmania tropica is one of the main causative agents of cutaneous leishmaniasis (CL). Population structures of L. tropica appear to be genetically highly diverse. However, the relationship between L. tropica strains genomic diversity, protein coding gene evolution and biogeography are still poorly understood. In this study, we sequenced the genomes of three new clinical L. tropica isolates, two derived from a recent outbreak of CL in camps hosting Syrian refugees in Lebanon and one historical isolate from Azerbaijan to further refine comparative genome analyses. In silico multilocus microsatellite typing (MLMT) was performed to integrate the current diversity of genome sequence data in the wider available MLMT genetic population framework. Single nucleotide polymorphism (SNPs), gene copy number variations (CNVs) and chromosome ploidy were investigated across the available 18 L. tropica genomes with a main focus on protein coding genes. MLMT divided the strains in three populations that broadly correlated with their geographical distribution but not populations defined by SNPs. Unique SNPs profiles divided the 18 strains into five populations based on principal component analysis. Gene ontology enrichment analysis of the protein coding genes with population specific SNPs profiles revealed various biological processes, including iron acquisition, sterols synthesis and drug resistance. This study further highlights the complex links between L. tropica important genomic heterogeneity and the parasite broad geographic distribution. Unique sequence features in protein coding genes identified in distinct populations reveal potential novel markers that could be exploited for the development of more accurate typing schemes to further improve our knowledge of the evolution and epidemiology of the parasite as well as highlighting protein variants of potential functional importance underlying L. tropica specific biology.