Structure of the Polycomb Group Protein PCGF1 in Complex with BCOR Reveals Basis for Binding Selectivity of PCGF Homologs

SummaryPolycomb-group RING finger homologs (PCGF1, PCGF2, PCGF3, PCGF4, PCGF5, and PCGF6) are critical components in the assembly of distinct Polycomb repression complex 1 (PRC1)-related complexes. Here, we identify a protein interaction domain in BCL6 corepressor, BCOR, which binds the RING finger- and WD40-associated ubiquitin-like (RAWUL) domain of PCGF1 (NSPC1) and PCGF3 but not of PCGF2 (MEL18) or PCGF4 (BMI1). Because of the selective binding, we have named this domain PCGF Ub-like fold discriminator (PUFD). The structure of BCOR PUFD bound to PCGF1 reveals that (1) PUFD binds to the same surfaces as observed for a different Polycomb group RAWUL domain and (2) the ability of PUFD to discriminate among RAWULs stems from the identity of specific residues within these interaction surfaces. These data show the molecular basis for determining the binding preference for a PCGF homolog, which ultimately helps determine the identity of the larger PRC1-like assembly

Comparative growth and biomass allocation of two varieties of cat's claw creeper, Dolichandra unguis-cati (Bignoniaceae) in Australia

Introduced as an ornamental vine, cat's claw creeper Dolichandra unguis-cati (syn. Macfadyena unguis-cati) has invaded coastal and subcoastal areas of subtropical eastern Australia. Two varieties have been indentified, one of which ('short-pod') is found throughout south-eastern Australia, while the other ('long-pod') appears to be restricted to several sites in south-eastern Queensland. We compared the growth and biomass allocation patterns of the two varieties in the field over a 22-month period to determine if a higher growth rate and/or more efficient allocation of biomass may contribute to this disparity in distribution. The long-pod variety produced greater aboveground and total biomass than the short-pod variety in both riparian and non-riparian zones. Belowground the two varieties produced a similar number of tubers and overall biomass, though the long-pod variety allocated a smaller portion of its carbon belowground. High growth rates and greater biomass allocation aboveground are characteristic of invasive species, allowing them to outcompete and crowd out existing vegetation. There was no significant site by variety interaction, an indication of consistency in variety performance across riparian and non-riparian sites. Results from our study suggest that differences in growth and biomass allocations are unlikely to have contributed to the disparity in distribution of the two varieties. Despite currently occupying a relatively small range, the long-pod variety may be a more adept invader than the short-pod variety, and could become more prevalent in the future. © 2012 CSIRO

Stromal cell-derived factor and granulocyte-monocyte colony-stimulating factor form a combined neovasculogenic therapy for ischemic cardiomyopathy

ObjectiveIschemic heart failure is an increasingly prevalent global health concern with major morbidity and mortality. Currently, therapies are limited, and novel revascularization methods might have a role. This study examined enhancing endogenous myocardial revascularization by expanding bone marrow-derived endothelial progenitor cells with the marrow stimulant granulocyte-monocyte colony-stimulating factor and recruiting the endothelial progenitor cells with intramyocardial administration of the potent endothelial progenitor cell chemokine stromal cell-derived factor.MethodsIschemic cardiomyopathy was induced in Lewis rats (n = 40) through left anterior descending coronary artery ligation. After 3 weeks, animals were randomized into 4 groups: saline control, granulocyte-monocyte colony-stimulating factor only (GM-CSF only), stromal cell-derived factor only (SDF only), and combined stromal cell-derived factor/granulocyte-monocyte colony-stimulating factor (SDF/GM-CSF) (n = 10 each). After another 3 weeks, hearts were analyzed for endothelial progenitor cell density by endothelial progenitor cell marker colocalization immunohistochemistry, vasculogenesis by von Willebrand immunohistochemistry, ventricular geometry by hematoxylin-and-eosin microscopy, and in vivo myocardial function with an intracavitary pressure-volume conductance microcatheter.ResultsThe saline control, GM-CSF only, and SDF only groups were equivalent. Compared with the saline control group, animals in the SDF/GM-CSF group exhibited increased endothelial progenitor cell density (21.7 ± 3.2 vs 9.6 ± 3.1 CD34+/vascular endothelial growth factor receptor 2–positive cells per high-power field, P = .01). There was enhanced vascularity (44.1 ± 5.5 versus 23.8 ± 2.2 von Willebrand factor-positive vessels per high-power field, P = .007). SDF/GM-CSF group animals experienced less adverse ventricular remodeling, as manifested by less cavitary dilatation (9.8 ± 0.1 mm vs 10.1 ± 0.1 mm [control], P = .04) and increased border-zone wall thickness (1.78 ± 0.19 vs 1.41 ± 0.16 mm [control], P = .03). (SDF/GM-CSF group animals had improved cardiac function compared with animals in the saline control group (maximum pressure: 93.9 ± 3.2 vs 71.7 ± 3.1 mm Hg, P < .001; maximum dP/dt: 3513 ± 303 vs 2602 ± 201 mm Hg/s, P < .05; cardiac output: 21.3 ± 2.7 vs 13.3 ± 1.3 mL/min, P < .01; end-systolic pressure-volume relationship slope: 1.7 ± 0.4 vs 0.5 ± 0.2 mm Hg/μL, P < .01.)ConclusionThis novel revascularization strategy of bone marrow stimulation and intramyocardial delivery of the endothelial progenitor cell chemokine stromal cell-derived factor yielded significantly enhanced myocardial endothelial progenitor cell density, vasculogenesis, geometric preservation, and contractility in a model of ischemic cardiomyopathy

Ancient and novel small RNA pathways compensate for the loss of piRNAs in multiple independent nematode lineages.

Small RNA pathways act at the front line of defence against transposable elements across the Eukaryota. In animals, Piwi interacting small RNAs (piRNAs) are a crucial arm of this defence. However, the evolutionary relationships among piRNAs and other small RNA pathways targeting transposable elements are poorly resolved. To address this question we sequenced small RNAs from multiple, diverse nematode species, producing the first phylum-wide analysis of how small RNA pathways evolve. Surprisingly, despite their prominence in Caenorhabditis elegans and closely related nematodes, piRNAs are absent in all other nematode lineages. We found that there are at least two evolutionarily distinct mechanisms that compensate for the absence of piRNAs, both involving RNA-dependent RNA polymerases (RdRPs). Whilst one pathway is unique to nematodes, the second involves Dicer-dependent RNA-directed DNA methylation, hitherto unknown in animals, and bears striking similarity to transposon-control mechanisms in fungi and plants. Our results highlight the rapid, context-dependent evolution of small RNA pathways and suggest piRNAs in animals may have replaced an ancient eukaryotic RNA-dependent RNA polymerase pathway to control transposable elements.We thank Sylviane Moss for high-throughput sequencing support. We thank Charles Bradshaw for help with computation and IT. We thank Marie-Anne Felix and Frank Jiggins for critical comments on the manuscript. We thank Matt Berriman (Wellcome Trust Sanger Centre, Hinxton, Cambridge, UK) for allowing us to use unpublished genomic sequencing data for N. brasiliensis. We thank Einhardt Schierenberg (University of Cologne, Germany) and Werner Armonies (Alfred Wegener Institute, Sylt, Germany) for help with collection of E. brevis.This is the final version of the article, originally published in PLoS Biology, 2015, 13(2): e1002061. doi:10.1371/journal.pbio.100206

The C. elegans ephrin EFN-4 functions non-cell autonomously with heparan sulfate proteoglycans to promote axon outgrowth and branching

The Eph receptors and their cognate ephrin ligands play key roles in many aspects of nervous system development. These interactions typically occur within an individual tissue type, serving either to guide axons to their terminal targets or to define boundaries between the rhombomeres of the hindbrain. We have identified a novel role for the Caenorhabditis elegans ephrin EFN-4 in promoting primary neurite outgrowth in AIY interneurons and D-class motor neurons. Rescue experiments reveal that EFN-4 functions non-cell autonomously in the epidermis to promote primary neurite outgrowth. We also find that EFN-4 plays a role in promoting ectopic axon branching in a C. elegans model of X-linked Kallmann syndrome. In this context, EFN-4 functions non-cell autonomously in the body wall muscle, and in parallel with HS biosynthesis genes and HSPG core proteins, which function cell autonomously in the AIY neurons. This is the first report of an epidermal ephrin providing a developmental cue to the nervous system

Antidepressants during and after Menopausal Transition: A Systematic Review and Meta-Analysis

To assess the therapeutic benefits of antidepressants in depressive women during and after menopausal transition, PubMed, Cochrane Library, EMBASE and Science Direct were systematically searched from inception to February 1, 2020 for randomized controlled trials examining antidepressants compared to placebo. Primary outcome was change in depressive symptom severity, while secondary outcomes were rates of response/remission rates and dropout/discontinuation due to adverse events. Seven trials involving 1,676 participants (mean age = 52.6 years) showed significant improvement in depressive symptoms (k = 7, Hedges’ g = 0.44, 95% confidence interval (CI) = 0.32 to 0.57, p < 0.001) relative to that in controls. Furthermore, response (k = 3, odds ratio (OR) = 2.53, 95% CI = 1.24 to 5.15, p = 0.01) and remission (k = 3, OR = 1.84, 95% CI = 1.32 to 2.57, p < 0.001) rates were significantly higher in antidepressant-treated groups compared to those with controls. Although dropout rates did not differ between antidepressant and control groups (k = 6, OR = 0.93, 95% CI = 0.70 to 1.26, p = 0.68), the rate of discontinuation due to adverse events was significantly higher in antidepressant-treated groups (k = 6, OR = 0.55, 95% CI = 0.35 to 0.86, p = 0.01). Subgroup analysis indicated that antidepressants were also efficacious for depressive symptoms in those without diagnosis of MDD. The results demonstrated that antidepressants were efficacious for women with depressive syndromes during and after menopausal transition but associated with a higher risk of discontinuation due to adverse events

KDM2B recruitment of the polycomb group complex, PRC1.1, requires cooperation between PCGF1 and BCORL1

Accepted author manuscriptKDM2B recruits H2A-ubiquitinating activity of a non-canonical Polycomb Repression Complex 1 (PRC1.1) to CpG islands, facilitating gene repres sion. We investigated the molecular basis of recruit ment using in vitro assembly assays to identify minimal components, subcomplexes, and domains required for recruitment. A minimal four-component PRC1.1 complex can be assembled by combining two separately isolated subcomplexes: the DNA binding KDM2B/SKP1 heterodimer and the hetero dimer of BCORL1 and PCGF1, a core component of PRC1.1. The crystal structure of the KDM2B/ SKP1/BCORL1/PCGF1 complex illustrates the crucial role played by the PCGF1/BCORL1 hetero dimer. The BCORL1 PUFD domain positions resi dues preceding the RAWUL domain of PCGF1 to create an extended interface for interaction with KDM2B, which is unique to the PCGF1-containing PRC1.1 complex. The structure also suggests how KDM2B might simultaneously function in PRC1.1 and an SCF ubiquitin ligase complex and the possible molecular consequences of BCOR PUFD internal tandem duplications found in pediatric kidney and brain tumors.Ye