Orbital mucosa-associated lymphoid tissue (MALT) lymphoma as the initial presentation in patients with hepatitis C virus infection.

Hepatitis C virus infection may be implicated in 12.7% of ocular adnexal marginal zone lymphomas. We present the first case of an orbital-systemic mucosa-associated lymphoid tissue lymphoma that responded to hepatitis C virus medical treatment. A 62-year-old male with a right-sided orbital mass was diagnosed with stage IIA orbital marginal zone lymphoma in addition to hepatitis C virus infection based on clinical, imaging, laboratory, and histological examinations. The systemic and orbital responses were achieved 1 year after undergoing hepatitis C virus treatment with glecaprevir/pibrentasvir. The association between the hepatitis C virus infection and orbital-systemic mucosa-associated lymphoid tissue lymphoma is relevant. Accordingly, patients with orbital mucosa-associated lymphoid tissue lymphoma should be assessed for hepatitis C virus seroreactivity for therapeutic and prognostic purposes.

Orbital mucosa-associated lymphoid tissue (MALT) lymphoma as the initial presentation in patients with hepatitis C virus infection

ABSTRACT Hepatitis C virus infection may be implicated in 12.7% of ocular adnexal marginal zone lymphomas. We present the first case of an orbital-systemic mucosa-associated lymphoid tissue lymphoma that responded to hepatitis C virus medical treatment. A 62-year-old male with a right-sided orbital mass was diagnosed with stage IIA orbital marginal zone lymphoma in addition to hepatitis C virus infection based on clinical, imaging, laboratory, and histological examinations. The systemic and orbital responses were achieved 1 year after undergoing hepatitis C virus treatment with glecaprevir/pibrentasvir. The association between the hepatitis C virus infection and orbital-systemic mucosa-associated lymphoid tissue lymphoma is relevant. Accordingly, patients with orbital mucosa-associated lymphoid tissue lymphoma should be assessed for hepatitis C virus seroreactivity for therapeutic and prognostic purposes.

Distantly related Alteromonas bacteriophages share tail fibers exhibiting properties of transient chaperone caps.

The host recognition modules encoding the injection machinery and receptor binding proteins (RBPs) of bacteriophages are predisposed to mutation and recombination to maintain infectivity towards co-evolving bacterial hosts. In this study, we reveal how Alteromonas mediterranea schitovirus A5 shares its host recognition module, including tail fiber and cognate chaperone, with phages from distantly related families including Alteromonas myovirus V22. While the V22 chaperone is essential for producing active tail fibers, here we demonstrate production of functional A5 tail fibers regardless of chaperone co-expression. AlphaFold-generated models of tail fiber and chaperone pairs from phages A5, V22, and other Alteromonas phages reveal how amino acid insertions within both A5-like proteins results in a knob domain duplication in the tail fiber and a chaperone ß-hairpin "tentacle" extension. These structural modifications are linked to differences in chaperone dependency between the A5 and V22 tail fibers. Structural similarity between the chaperones and intramolecular chaperone domains of other phage RBPs suggests an additional function of these chaperones as transient fiber "caps". Finally, our identification of homologous host recognition modules from morphologically distinct phages implies that horizontal gene transfer and recombination events between unrelated phages may be a more common process than previously thought among Caudoviricetes phages.

Microbial community on industrial salty bovine hides: From the slaughterhouse to the salting.

The leather-making industry is an age-old industry and desiccation with salt has been one of the most used methodologies for obtaining valuable skins. However, halophiles may proliferate and affect the integrity of the hide-collagen structure, as well as leading to undesirable red colorations or less-frequent purple stains. To understand the basis of these industrial hide contaminations, the microbial community from raw hide samples, salt-cured samples and four different industrial salts, was analyzed by 16S rRNA gene metabarcoding together with standard cultivation methods. Comparison of raw hides and correctly cured hides revealed a core microbiome that was absent from contaminated hides. In addition, archaea were missing from well-cured hides, whereas Psychrobacter and Acinetobacter were highly represented (23 % and 17.4 %, respectively). In damaged hides, only a few operational taxonomic units (OTUs), from among the hundreds detected, were able to proliferate and, remarkably, a single Halomonas OTU represented 57.66 % of the reads. Halobacteria, mainly Halovenus, Halorubrum and Halovivax, increased by up to 36.24-39.5 % in the red- and purple-affected hides. The major contaminants were isolated and hide infections, together with collagenase activity, were evaluated. The results showed that hides enriched with the non-pigmented isolate Halomonas utahensis COIN160 damaged the collagen fibers similarly to Halorubrum, and together they were considered to be one of the major causes. Putative degrading inhibitors were also identified from among the Alkalibacillus isolates. It was concluded that hide contaminations were driven by clonal outbreaks of a few specific microbes, which may have been non-pigmented collagen degraders. Acinetobacter and Alkalibacillus, members of the core microbiome of raw and well-cured salted hides, are suggested as hide contaminant inhibitors that need further analysis.

Different NIPBL requirements of cohesin-STAG1 and cohesin-STAG2.

Cohesin organizes the genome through the formation of chromatin loops. NIPBL activates cohesin's ATPase and is essential for loop extrusion, but its requirement for cohesin loading is unclear. Here we have examined the effect of reducing NIPBL levels on the behavior of the two cohesin variants carrying STAG1 or STAG2 by combining a flow cytometry assay to measure chromatin-bound cohesin with analyses of its genome-wide distribution and genome contacts. We show that NIPBL depletion results in increased cohesin-STAG1 on chromatin that further accumulates at CTCF positions while cohesin-STAG2 diminishes genome-wide. Our data are consistent with a model in which NIPBL may not be required for chromatin association of cohesin but it is for loop extrusion, which in turn facilitates stabilization of cohesin-STAG2 at CTCF positions after being loaded elsewhere. In contrast, cohesin-STAG1 binds chromatin and becomes stabilized at CTCF sites even under low NIPBL levels, but genome folding is severely impaired.

Contribution of variant subunits and associated factors to genome-wide distribution and dynamics of cohesin.

BACKGROUND: The cohesin complex organizes the genome-forming dynamic chromatin loops that impact on all DNA-mediated processes. There are two different cohesin complexes in vertebrate somatic cells, carrying the STAG1 or STAG2 subunit, and two versions of the regulatory subunit PDS5, PDS5A and PDS5B. Mice deficient for any of the variant subunits are embryonic lethal, which indicates that they are not functionally redundant. However, their specific behavior at the molecular level is not fully understood. RESULTS: The genome-wide distribution of cohesin provides important information with functional consequences. Here, we have characterized the distribution of cohesin subunits and regulators in mouse embryo fibroblasts (MEFs) either wild type or deficient for cohesin subunits and regulators by chromatin immunoprecipitation and deep sequencing. We identify non-CTCF cohesin-binding sites in addition to the commonly detected CTCF cohesin sites and show that cohesin-STAG2 is the preferred variant at these positions. Moreover, this complex has a more dynamic association with chromatin as judged by fluorescence recovery after photobleaching (FRAP), associates preferentially with WAPL and is more easily extracted from chromatin with salt than cohesin-STAG1. We observe that both PDS5A and PDS5B are exclusively located at cohesin-CTCF positions and that ablation of a single paralog has no noticeable consequences for cohesin distribution while double knocked out cells show decreased accumulation of cohesin at all its binding sites. With the exception of a fraction of cohesin positions in which we find binding of all regulators, including CTCF and WAPL, the presence of NIPBL and PDS5 is mutually exclusive, consistent with our immunoprecipitation analyses in mammalian cell extracts and previous results in yeast. CONCLUSION: Our findings support the idea that non-CTCF cohesin-binding sites represent sites of cohesin loading or pausing and are preferentially occupied by the more dynamic cohesin-STAG2. PDS5 proteins redundantly contribute to arrest cohesin at CTCF sites, possibly by preventing binding of NIPBL, but are not essential for this arrest. These results add important insights towards understanding how cohesin regulates genome folding and the specific contributions of the different variants that coexist in the cell.

Differences in gene expression patterns between cultured and natural Haloquadratum walsbyi ecotypes.

Solar crystallizer ponds are characterized by high population density with a relatively simple community structure in terms of species composition. The microbial community in the solar saltern of Santa Pola (Alicante, Spain), is largely dominated by the hyperhalophilic square archaeon Haloquadratum walsbyi. Here we studied metatranscriptomes retrieved from a crystallizer pond during the winter of 2012 and summer of 2014 and compared Hqr. walsbyi's transcription patterns with that of the cultured strain Hqr. walsbyi HBSQ001. Significant differences were found between natural and the cultured grown strain in the distribution of transcript levels per gene. This likely reflects the adaptation of the cultured strain to the relative homogeneous growth conditions while the natural species, which is represented by multiple ecotypes, is adapted to heterogeneous environmental conditions and challenges of nutrient competition, viral attack, and other stressors. An important consequence of this study is that expression patterns obtained under artificial cultivation conditions cannot be directly extrapolated to gene expression under natural conditions. Moreover, we found 195 significantly differential expressed genes between the seasons, with 140 genes being higher expressed in winter and mainly encode proteins involved in energy and carbon source acquiring processes, and in stress responses.

Establishment of 3D chromatin structure after fertilization and the metabolic switch at the morula-to-blastocyst transition require CTCF.

The eukaryotic genome is organized in 3D at different scales. This structure is driven and maintained by different chromatin states and by architectural factors, such as the zinc finger protein CTCF. Zygotic genome structure is established de novo after fertilization, but its impact during the first stages of mammalian development is unclear. We show that deletion of Ctcf in mouse embryos impairs the establishment of chromatin structure, but the first cell fate decision is unperturbed and embryos are viable until the late blastocyst. Furthermore, maternal CTCF is not necessary for development. Gene expression changes in metabolic and protein homeostasis programs that occur during the morula-to-blastocyst transition depend on CTCF. However, these changes do not correlate with disruption of chromatin but with binding of CTCF to the promoter of downregulated genes. Our results show that CTCF regulates both 3D genome organization and transcription during mouse preimplantation development, but as independent processes.

Training Plan for the Continuity of Non-Presential Education in Six Peruvian Universities during COVID-19.

This article shows the response offered by the UTEC-UNED-TECSUP Consortium to six Peruvian public (national) universities aimed at strengthening the digital competences of their communities, made up of managers, teachers, students, and support technicians. The contextual and situational diagnosis, which covered organizational, technological, and competence dimensions, revealed a series of cross-cutting needs related to technological skills that prevented the training or mobilization of the digital competences necessary for progress in the other dimensions under study. The response was an online training plan, consisting of three training programs and eighty-three courses. The pedagogical strategy was based on the scaling of competence achievements that ended with problem-solving and applications in daily activities. The accompaniment was carried out through virtual tutorials, distributed via synchronous and asynchronous sessions. In total, 5034 were involved-347 were teachers and managers, 4932 were students, and 25 were technical staff. The pedagogical and socio-emotional limitations of the university community, as well as the scarcity of technological resources and poor connectivity, meant that the plan was only partially implemented. Moreover, the short and intense period of development to which the universities were subjected was also a factor.

Metagenomics Unveils Posidonia oceanica "Banquettes" as a Potential Source of Novel Bioactive Compounds and Carbohydrate Active Enzymes (CAZymes).

Posidonia oceanica is a long-living and very slow-growing marine seagrass endemic to the Mediterranean Sea. It produces large amounts of leaf material and rhizomes, which can reach the shore and build important banks known as "banquettes." In recent years, interest in the potential uses of these P. oceanica banquettes has increased, and it was demonstrated that biomass extracts showed antioxidant, antifungal, and antiviral activities. The discovery of new compounds through the culture of microorganisms is limited, and to overcome this limitation, we performed a metagenomic study to investigate the microbial community associated with P. oceanica banquettes. Our results showed that the microbial community associated with P. oceanica banquettes was dominated by Alphaproteobacteria, Gammaproteobacteria, Bacteroidetes, and Cyanobacteria. Pseudoalteromonas was the dominant genus, followed by Alteromonas, Labrenzia, and Aquimarina. The metagenome reads were binned and assembled into 23 nearly complete metagenome-assembled genomes (MAGs), which belonged to new families of Cyanobacteria, Myxococcota, and Granulosicoccaceae and also to the novel genus recently described as Gammaproteobacteria family UBA10353. A comparative analysis with 60 published metagenomes from different environments, including seawater, marine biofilms, soils, corals, sponges, and hydrothermal vents, indicated that banquettes have numbers of natural products and carbohydrate active enzymes (CAZymes) similar to those found for soils and were only surpassed by marine biofilms. New proteins assigned to cellulosome modules and lignocellulose-degrading enzymes were also found. These results unveiled the diverse microbial composition of P. oceanica banquettes and determined that banquettes are a potential source of bioactive compounds and novel enzymes. IMPORTANCE Posidonia oceanica is a long-living and very slow-growing marine seagrass endemic to the Mediterranean Sea that forms large amounts of leaf material and rhizomes, which can reach the shore and build important banks known as "banquettes." These banquettes accumulate on the shore, where they can prevent erosion, although they also cause social concern due to their impact on beach use. Furthermore, Posidonia dry material has been considered a source of traditional remedies in several areas of the Mediterranean, and a few studies have been carried out to explore pharmacological activities of Posidonia extracts. The work presented here provides the first characterization of the microbiome associated with Posidonia banquettes. We carried out a metagenomic analysis together with an in-depth comparison of the banquette metagenome with 60 published metagenomes from different environments. This comparative analysis has unveiled the potential that Posidonia banquettes have for the synthesis of natural products, both in abundance (only surpassed by marine biofilms) and novelty. These products include mainly nonribosomal peptides and carbohydrate active enzymes. Thus, the interest of our work lies in the interest of Posidonia "waste" material as a source of new bioactive compounds and CAZymes.

Disruption of NIPBL/Scc2 in Cornelia de Lange Syndrome provokes cohesin genome-wide redistribution with an impact in the transcriptome.

Cornelia de Lange syndrome (CdLS) is a rare disease affecting multiple organs and systems during development. Mutations in the cohesin loader, NIPBL/Scc2, were first described and are the most frequent in clinically diagnosed CdLS patients. The molecular mechanisms driving CdLS phenotypes are not understood. In addition to its canonical role in sister chromatid cohesion, cohesin is implicated in the spatial organization of the genome. Here, we investigate the transcriptome of CdLS patient-derived primary fibroblasts and observe the downregulation of genes involved in development and system skeletal organization, providing a link to the developmental alterations and limb abnormalities characteristic of CdLS patients. Genome-wide distribution studies demonstrate a global reduction of NIPBL at the NIPBL-associated high GC content regions in CdLS-derived cells. In addition, cohesin accumulates at NIPBL-occupied sites at CpG islands potentially due to reduced cohesin translocation along chromosomes, and fewer cohesin peaks colocalize with CTCF.

Regulatory CDH4 Genetic Variants Associate With Risk to Develop Capecitabine-Induced Hand-Foot Syndrome.

Capecitabine-induced hand-foot syndrome (CiHFS) is a common dermatological adverse reaction affecting around 30% of patients with capecitabine-treated cancer, and the main cause of dose reductions and chemotherapy delays. To identify novel genetic factors associated with CiHFS in patients with cancer, we carried out an extreme-phenotype genomewide association study in 166 patients with breast and colorectal capecitabine-treated cancer with replication in a second cohort of 85 patients. We discovered and replicated a cluster of four highly correlated single-nucleotide polymorphisms associated with susceptibility to CiHFS at 20q13.33 locus (top hit = rs6129058, hazard ratio = 2.40, 95% confidence interval = 1.78-3.20; P = 1.2 × 10-8 ). Using circular chromosome conformation capture sequencing, we identified a chromatin contact between the locus containing the risk alleles and the promoter of CDH4, located 90 kilobases away. The risk haplotype was associated with decreased levels of CDH4 mRNA and the protein it encodes, R-cadherin (RCAD), which mainly localizes in the granular layer of the epidermis. In human keratinocytes, CDH4 downregulation resulted in reduced expression of involucrin, a protein of the cornified envelope, an essential structure for skin barrier function. Immunohistochemical analyses revealed that skin from patients with severe CiHFS exhibited low levels of RCAD and involucrin before capecitabine treatment. Our results uncover a novel mechanism underlying individual genetic susceptibility to CiHFS with implications for clinically relevant risk prediction.

Mapeando los activos en salud de mi barrio: nuestra experiencia / Mapping out healthcare assets in my neighbourhood: our experience

INTRODUCCIÓN: el modelo de los activos comunitarios se caracteriza por fomentar condiciones de salud que potencian las capacidades y habilidades individuales y colectivas. El objetivo de este proyecto ha sido identificar el mapa de activos en salud del barrio Arturo Eyries de Valladolid, para promover la prescripción social por parte del personal sanitario y hacer más visibles los recursos de los que dispone la comunidad. METODOLOGÍA: se han utilizado diferentes técnicas de mapeo: búsqueda de datos en internet, redes sociales, periódicos, paseos por el barrio, entrevistas, mapas mudos y fotovoz. Se incluyeron pacientes y profesionales sanitarios del Centro de Salud Arturo Eyries. RESULTADOS: se ha recogido información de un total de 40 participantes: 10 profesionales sanitarios y 30 pacientes del centro de salud. El resultado de esta investigación fueron 37 activos clasificados en seis categorías: sanidad, ocio y cultura, apoyo social, educación, ejercicio físico y transporte. Con todo esto se ha creado un fichero de activos, un mapa del barrio, una página web, un tríptico y una sesión clínica para los profesionales del centro. CONCLUSIONES: este proyecto de mapeo constituye el punto de partida para mejorar el conocimiento que los profesionales sanitarios y los pacientes tienen sobre los recursos de salud de su entorno. Este trabajo representa el inicio de una red para la promoción de la salud, dirigida a implicar a instituciones y responsables políticos en la creación de una cartografía común, a nivel ciudad o incluso comunidad autónoma, de activos para la salud

INTRODUCTION: The community assets model is characterized by fostering health conditions that enhance individual and collective capacities and abilities. The aim of this project has been to identify the map of health assets in the Arturo Eyries neighbourhood of Valladolid to promote social prescription by health personnel, and to make the resources available to the community more visible. METHODOLOGY: Different mapping techniques have been used: internet data search, social networks, newspapers, walks around the neighbourhood, interviews, silent maps and photovoice. Patients and health professionals from the Arturo Eyries health centre were included in this study. RESULTS: Information was collected from a total of 40 participants: 10 health professionals and 30 health centre patients. The result of this research was 37 assets classified into six categories: health, leisure and culture, social support, education, physical exercise and transport. With all this, an asset file, a map of the neighbourhood, a web page, a leaflet and a clinical session for the centre's professionals were created. CONCLUSIONS: This mapping project is the starting point for improving the knowledge that health professionals and patients have about the health resources of their environment. This work represents the beginning of a network for health promotion, and we would like to involve institutions and the politicians in the creation of common mapping, at local or regional level, of health assets

Virulence as a Side Effect of Interspecies Interaction in Vibrio Coral Pathogens.

The increase in prevalence and severity of coral disease outbreaks produced by Vibrio pathogens, and related to global warming, has seriously impacted reef-building corals throughout the oceans. The coral Oculina patagonica has been used as a model system to study coral bleaching produced by Vibrio infection. Previous data demonstrated that when two coral pathogens (Vibrio coralliilyticus and Vibrio mediterranei) simultaneously infected the coral O. patagonica, their pathogenicity was greater than when each bacterium was infected separately. Here, to understand the mechanisms underlying this synergistic effect, transcriptomic analyses of monocultures and cocultures as well as experimental infection experiments were performed. Our results revealed that the interaction between the two vibrios under culture conditions overexpressed virulence factor genes (e.g., those encoding siderophores, the type VI secretion system, and toxins, among others). Moreover, under these conditions, vibrios were also more likely to form biofilms or become motile through induction of lateral flagella. All these changes that occur as a physiological response to the presence of a competing species could favor the colonization of the host when they are present in a mixed population. Additionally, during coral experimental infections, we showed that exposure of corals to molecules released during V. coralliilyticus and V. mediterranei coculture induced changes in the coral microbiome that favored damage to coral tissue and increased the production of lyso-platelet activating factor. Therefore, we propose that competition sensing, defined as the physiological response to detection of harm or to the presence of a competing Vibrio species, enhances the ability of Vibrio coral pathogens to invade their host and cause tissue necrosis.IMPORTANCEVibrio coralliilyticus and Vibrio mediterranei are important coral pathogens capable of inducing serious coral damage, which increases severely when they infect the host simultaneously. This has consequences related to the dispersion of these pathogens among different locations that could enhance deleterious effects on coral reefs. However, the mechanisms underlying this synergistic interaction are unknown. The work described here provides a new perspective on the complex interactions among these two Vibrio coral pathogens, suggesting that coral infection could be a collateral effect of interspecific competition. Major implications of this work are that (i) Vibrio virulence mechanisms are activated in the absence of the host as a response to interspecific competition and (ii) release of molecules by Vibrio coral pathogens produces changes in the coral microbiome that favor the pathogenic potential of the entire Vibrio community. Thus, our results highlight that social cues and competition sensing are crucial determinants of development of coral diseases.

Estrategia para la Eliminación de la Hepatitis C en Cantabria / No disponible

No disponible

Alteromonas Myovirus V22 Represents a New Genus of Marine Bacteriophages Requiring a Tail Fiber Chaperone for Host Recognition.

Marine phages play a variety of critical roles in regulating the microbial composition of our oceans. Despite constituting the majority of genetic diversity within these environments, there are relatively few isolates with complete genome sequences or in-depth analyses of their host interaction mechanisms, such as characterization of their receptor binding proteins (RBPs). Here, we present the 92,760-bp genome of the Alteromonas-targeting phage V22. Genomic and morphological analyses identify V22 as a myovirus; however, due to a lack of sequence similarity to any other known myoviruses, we propose that V22 be classified as the type phage of a new Myoalterovirus genus within the Myoviridae family. V22 shows gene homology and synteny with two different subfamilies of phages infecting enterobacteria, specifically within the structural region of its genome. To improve our understanding of the V22 adsorption process, we identified putative RBPs (gp23, gp24, and gp26) and tested their ability to decorate the V22 propagation strain, Alteromonas mediterranea PT11, as recombinant green fluorescent protein (GFP)-tagged constructs. Only GFP-gp26 was capable of bacterial recognition and identified as the V22 RBP. Interestingly, production of functional GFP-gp26 required coexpression with the downstream protein gp27. GFP-gp26 could be expressed alone but was incapable of host recognition. By combining size-exclusion chromatography with fluorescence microscopy, we reveal how gp27 is not a component of the final RBP complex but instead is identified as a new type of phage-encoded intermolecular chaperone that is essential for maturation of the gp26 RBP.IMPORTANCE Host recognition by phage-encoded receptor binding proteins (RBPs) constitutes the first step in all phage infections and the most critical determinant of host specificity. By characterizing new types of RBPs and identifying their essential chaperones, we hope to expand the repertoire of known phage-host recognition machineries. Due to their genetic plasticity, studying RBPs and their associated chaperones can shed new light onto viral evolution affecting phage-host interactions, which is essential for fields such as phage therapy or biotechnology. In addition, since marine phages constitute one of the most important reservoirs of noncharacterized genetic diversity on the planet, their genomic and functional characterization may be of paramount importance for the discovery of novel genes with potential applications.

Specialized functions of cohesins STAG1 and STAG2 in 3D genome architecture.

Cohesin is a complex conserved in evolution that entraps DNA. Originally identified for its role in sister chromatid cohesion, it is currently considered a key player in 3D genome organization. In vertebrates, two paralog genes encode two versions of the SA/STAG subunit of cohesin, STAG1 and STAG2. While the existence of two variant complexes has been largely ignored in many cohesin studies, the high frequency of STAG2 mutations in cancer has stirred up the interest in dissecting the unique properties that the STAG proteins confer on cohesin. In this review, we summarize recent progress in our understanding of the functional specificity of cohesin-STAG1 and cohesin-STAG2 with particular emphasis on their contributions to genome organization and gene regulation.

Transcriptome dynamics of the Myxococcus xanthus multicellular developmental program.

The bacterium Myxococcus xanthus exhibits a complex multicellular life cycle. In the presence of nutrients, cells prey cooperatively. Upon starvation, they enter a developmental cycle wherein cells aggregate to produce macroscopic fruiting bodies filled with resistant myxospores. We used RNA-Seq technology to examine the transcriptome of the 96 hr developmental program. These data revealed that 1415 genes were sequentially expressed in 10 discrete modules, with expression peaking during aggregation, in the transition from aggregation to sporulation, or during sporulation. Analysis of genes expressed at each specific time point provided insights as to how starving cells obtain energy and precursors necessary for assembly of fruiting bodies and into developmental production of secondary metabolites. This study offers the first global view of developmental transcriptional profiles and provides important tools and resources for future studies.

Specific Contributions of Cohesin-SA1 and Cohesin-SA2 to TADs and Polycomb Domains in Embryonic Stem Cells.

Cohesin exists in two variants carrying either STAG/SA1 or SA2. Here we have addressed their specific contributions to the unique spatial organization of the mouse embryonic stem cell genome, which ensures super-enhancer-dependent transcription of pluripotency factors and repression of lineage-specification genes within Polycomb domains. We find that cohesin-SA2 facilitates Polycomb domain compaction through Polycomb repressing complex 1 (PRC1) recruitment and promotes the establishment of long-range interaction networks between distant Polycomb-bound promoters that are important for gene repression. Cohesin-SA1, in contrast, disrupts these networks, while preserving topologically associating domain (TAD) borders. The diverse effects of both complexes on genome topology may reflect two modes of action of cohesin. One, likely involving loop extrusion, establishes overall genome arrangement in TADs together with CTCF and prevents excessive segregation of same-class compartment regions. The other is required for organization of local transcriptional hubs such as Polycomb domains and super-enhancers, which define cell identity.