The stimulation of trimethylation of histone H3 Lys4 (H3K4) by H2B monoubiquitination (H2Bub) has been widely studied, with multiple mechanisms having been proposed for this form of histone ...cross-talk. Cps35/Swd2 within COMPASS (complex of proteins associated with Set1) is considered to bridge these different processes. However, a truncated form of Set1 (762-Set1) is reported to function in H3K4 trimethylation (H3K4me3) without interacting with Cps35/Swd2, and such cross-talk is attributed to the n-SET domain of Set1 and its interaction with the Cps40/Spp1 subunit of COMPASS. Here, we used biochemical, structural, in vivo, and chromatin immunoprecipitation (ChIP) sequencing (ChIP-seq) approaches to demonstrate that Cps40/Spp1 and the n-SET domain of Set1 are required for the stability of Set1 and not the cross-talk. Furthermore, the apparent wild-type levels of H3K4me3 in the 762-Set1 strain are due to the rogue methylase activity of this mutant, resulting in the mislocalization of H3K4me3 from the promoter-proximal regions to the gene bodies and intergenic regions. We also performed detailed screens and identified yeast strains lacking H2Bub but containing intact H2Bub enzymes that have normal levels of H3K4me3, suggesting that monoubiquitination may not directly stimulate COMPASS but rather works in the context of the PAF and Rad6/Bre1 complexes. Our study demonstrates that the monoubiquitination machinery and Cps35/Swd2 function to focus COMPASS's H3K4me3 activity at promoter-proximal regions in a context-dependent manner.
Catalytic-inactivating mutations within the
enhancer H3K4 mono-methyltransferase Trr and its mammalian homologs, MLL3/4, cause only minor changes in gene expression compared with whole-gene deletions ...for these COMPASS members. To identify essential histone methyltransferase-independent functions of Trr, we screened to identify a minimal Trr domain sufficient to rescue Trr-null lethality and demonstrate that this domain binds and stabilizes Utx in vivo. Using the homologous MLL3/MLL4 human sequences, we mapped a short ∼80-amino-acid UTX stabilization domain (USD) that promotes UTX stability in the absence of the rest of MLL3/4. Nuclear UTX stability is enhanced when the USD is fused with the MLL4 HMG-box. Thus, COMPASS-dependent UTX stabilization is an essential noncatalytic function of Trr/MLL3/MLL4, suggesting that stabilizing UTX could be a therapeutic strategy for cancers with MLL3/4 loss-of-function mutations.
Allergic rhinitis affects half a billion people globally, including a fifth of the Australian population. As the foremost outdoor allergen source, ambient grass pollen exposure is likely to be ...altered by climate change. The AusPollen Partnership aimed to standardize pollen monitoring and examine broad-scale biogeographical and meteorological factors influencing interannual variation in seasonality of grass pollen aerobiology in Australia.
Daily airborne grass and other pollen concentrations in four eastern Australian cities separated by over 1700 km, were simultaneously monitored using Hirst-style samplers following the Australian Interim Pollen and Spore Monitoring Standard and Protocols over four seasons from 2016 to 2020. The grass seasonal pollen integral was determined. Gridded rainfall, temperature, and satellite-derived grassland sources up to 100 km from the monitoring site were analysed.
The complexity of grass pollen seasons was related to latitude with multiple major summer-autumn peaks in Brisbane, major spring and minor summer peaks in Sydney and Canberra, and single major spring peaks occurring in Melbourne. The subtropical site of Brisbane showed a higher proportion of grass out of total pollen than more temperate sites. The magnitude of the grass seasonal pollen integral was correlated with pasture greenness, rainfall and number of days over 30 °C, preceding and within the season, up to 100 km radii from monitoring sites.
Interannual fluctuations in Australian grass pollen season magnitude are strongly influenced by regional biogeography and both pre- and in-season weather. This first continental scale, Southern Hemisphere standardized aerobiology dataset forms the basis to track shifts in pollen seasonality, biodiversity and impacts on allergic respiratory diseases.
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•Few Southern Hemisphere sites monitor pollen limiting aerobiology knowledge. .•AusPollen partners (2016–2020) generated pollen records at four sites across climate zones.•Seasonal grass pollen loads varied with rainfall, temperature, and grassland greenness.•Outcomes underpin pollen forecasting and tracking of health and climate change impacts.
Mutations in the human NBEAL2 gene cause gray platelet syndrome (GPS), a bleeding diathesis characterized by a lack of α granules in platelets. The functions of the NBEAL2 protein have not been ...explored outside platelet biology, but there are reports of increased frequency of infection and abnormal neutrophil morphology in patients with GPS. We therefore investigated the role of NBEAL2 in immunity by analyzing the phenotype of Nbeal2-deficient mice. We found profound abnormalities in the Nbeal2-deficient immune system, particularly in the function of neutrophils and NK cells. Phenotyping of Nbeal2-deficient neutrophils showed a severe reduction in granule contents across all granule subsets. Despite this, Nbeal2-deficient neutrophils had an enhanced phagocyte respiratory burst relative to Nbeal2-expressing neutrophils. This respiratory burst was associated with increased expression of cytosolic components of the NADPH oxidase complex. Nbeal2-deficient NK cells were also dysfunctional and showed reduced degranulation. These abnormalities were associated with increased susceptibility to both bacterial (Staphylococcus aureus) and viral (murine CMV) infection in vivo. These results define an essential role for NBEAL2 in mammalian immunity.
Antibodies offer a powerful means to interrogate specific proteins in a complex milieu. However, antibody availability and reliability can be problematic, whereas epitope tagging can be impractical ...in many cases. To address these limitations, the Protein Capture Reagents Program (PCRP) generated over a thousand renewable monoclonal antibodies (mAbs) against human presumptive chromatin proteins. However, these reagents have not been widely field-tested. We therefore performed a screen to test their ability to enrich genomic regions via chromatin immunoprecipitation (ChIP) and a variety of orthogonal assays. Eight hundred eighty-seven unique antibodies against 681 unique human transcription factors (TFs) were assayed by ultra-high-resolution ChIP-exo/seq, generating approximately 1200 ChIP-exo data sets, primarily in a single pass in one cell type (K562). Subsets of PCRP mAbs were further tested in ChIP-seq, CUT&RUN, STORM super-resolution microscopy, immunoblots, and protein binding microarray (PBM) experiments. About 5% of the tested antibodies displayed high-confidence target (i.e., cognate antigen) enrichment across at least one assay and are strong candidates for additional validation. An additional 34% produced ChIP-exo data that were distinct from background and thus warrant further testing. The remaining 61% were not substantially different from background, and likely require consideration of a much broader survey of cell types and/or assay optimizations. We show and discuss the metrics and challenges to antibody validation in chromatin-based assays.
Copy number (CN) variation (CNV) has been shown to be common in regions of the genome coding for immune-related genes, and thus impacts upon polygenic autoimmunity. Low CN of FCGR3B has recently been ...associated with systemic lupus erythematosus (SLE). FcgammaRIIIb is a glycosylphosphatidylinositol-linked, low affinity receptor for IgG found predominantly on human neutrophils. We present novel data demonstrating that both in a family with FcgammaRIIIb-deficiency and in the normal population, FCGR3B CNV correlates with protein expression, with neutrophil uptake of and adherence to immune complexes, and with soluble serum FcgammaRIIIb. Reduced FcgammaRIIIb expression is thus likely to contribute to the impaired clearance of immune complexes, which is a feature of SLE, explaining the association between low FCGR3B CNV and SLE that we have confirmed in a Caucasian population. In contrast, antineutrophil cytoplasmic antibody-associated systemic vasculitis (AASV), a disease not associated with immune complex deposition, is associated with high FCGR3B CN. Thus, we define a role for FCGR3B CNV in immune complex clearance, a function that may explain why low FCGR3B CNV is associated with SLE, but not AASV. This is the first report of an association between disease-related gene CNV and variation in protein expression and function that may contribute to autoimmune disease susceptibility.
The phagocyte respiratory burst is crucial for innate immunity. The transfer of electrons to oxygen is mediated by a membrane-bound heterodimer, comprising gp91
and p22
subunits. Deficiency of either ...subunit leads to severe immunodeficiency. We describe Eros (essential for reactive oxygen species), a protein encoded by the previously undefined mouse gene
, and show that it is essential for host defense via the phagocyte NAPDH oxidase. Eros is required for expression of the NADPH oxidase components, gp91
and p22
Consequently,
-deficient mice quickly succumb to infection.
also contributes to the formation of neutrophil extracellular traps (NETS) and impacts on the immune response to melanoma metastases.
is an ortholog of the plant protein Ycf4, which is necessary for expression of proteins of the photosynthetic photosystem 1 complex, itself also an NADPH oxio-reductase. We thus describe the key role of the previously uncharacterized protein Eros in host defense.
The Nepal Demographic Health Survey (NDHS) in 2006 showed that more than half (56%) of the women with sexually transmitted infections (STIs), including HIV, in Nepal sought sexual health services. ...There is no such data for female sex workers (FSWs) and the limited studies on this group suggest they do not even use routine health services. This study explores FSWs use of sexual health services and the factors associated with their use and non-use of services.
This study aimed to explore the factors associated with utilisation of sexual health services by FSWs in the Kathmandu Valley of Nepal, and it used a mixed-method approach consisting of an interviewer administered questionnaire-based survey and in-depth interviews.
The questionnaire survey, completed with 425 FSWs, showed that 90% FSWs self-reported sickness, and (30.8%) reported symptoms of STIs. A quarter (25%) of those reporting STIs had never visited any health facilities especially for sexual health services preferring to use non-governmental clinics (72%), private clinics (50%), hospital (27%) and health centres (13%). Multiple regression analysis showed that separated, married and street- based FSWs were more likely to seek health services from the clinics or hospitals. In- depth interviews with 15 FSWs revealed that FSWs perceived that personal, structural and socio-cultural barriers, such as inappropriate clinic opening hours, discrimination, the judgemental attitude of the service providers, lack of confidentiality, fear of public exposure, and higher fees for the services as barriers to their access and utilisation of sexual health services.
FSWs have limited access to information and to health services, and operate under personal, structural and socio-cultural constraints. The 'education' to change individual behaviour, health worker and community perceptions, as well as the training of the health workers, is necessary.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Involvement of Human MOF in ATM Function Gupta, Arun; Sharma, Girdhar G.; Young, Charles S. H. ...
Molecular and Cellular Biology,
06/2005, Letnik:
25, Številka:
12
Journal Article
PDF
