The COMPASS (complex of proteins associated with Set1) complex represents the prototype of the SET1/MLL family of methyltransferases that controls gene transcription by H3K4 methylation (H3K4me). ...Although H2B monoubiquitination (H2Bub) is well known as a prerequisite histone mark for COMPASS activity, how H2Bub activates COMPASS remains unclear. Here, we report the cryoelectron microscopy (cryo-EM) structures of an extended COMPASS catalytic module (CM) bound to the H2Bub and free nucleosome. The COMPASS CM clamps onto the nucleosome disk-face via an extensive interface to capture the flexible H3 N-terminal tail. The interface also sandwiches a critical Set1 arginine-rich motif (ARM) that autoinhibits COMPASS. Unexpectedly, without enhancing COMPASS-nucleosome interaction, H2Bub activates the enzymatic assembly by packing against Swd1 and alleviating the inhibitory effect of the Set1 ARM upon fastening it to the acidic patch. By delineating the spatial configuration of the COMPASS-H2Bub-nucleosome assembly, our studies establish the structural framework for understanding the long-studied H2Bub-H3K4me histone modification crosstalk.
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•Cryo-EM structures of COMPASS bound to a H2B-ubiquitinated and unmodified nucleosome•COMPASS captures nucleosomes by extensive interfacing with both histones and DNA•The Set1 ARM helix autoinhibits COMPASS upon nucleosome binding•H2Bub allosterically activates COMPASS by anchoring to the Set1 ARM helix
The cryo-EM structures of the yeast COMPASS methyltransferase bound to H2Bub and unmodified nucleosomes reveal an arginine-rich motif in the catalytic subunit, whose autoinhibitory effect on the enzymatic complex is overridden by H2B-conjugated ubiquitin. The study sheds light on the mechanism of an evolutionarily conserved crosstalk between two histone modifications.
The SET1/MLL family of histone methyltransferases is conserved in eukaryotes and regulates transcription by catalyzing histone H3K4 mono-, di-, and tri-methylation. These enzymes form a common ...five-subunit catalytic core whose assembly is critical for their basal and regulated enzymatic activities through unknown mechanisms. Here, we present the crystal structure of the intact yeast COMPASS histone methyltransferase catalytic module consisting of Swd1, Swd3, Bre2, Sdc1, and Set1. The complex is organized by Swd1, whose conserved C-terminal tail not only nucleates Swd3 and a Bre2-Sdc1 subcomplex, but also joins Set1 to construct a regulatory pocket next to the catalytic site. This inter-subunit pocket is targeted by a previously unrecognized enzyme-modulating motif in Swd3 and features a doorstop-style mechanism dictating substrate selectivity among SET1/MLL family members. By spatially mapping the functional components of COMPASS, our results provide a structural framework for understanding the multifaceted functions and regulation of the H3K4 methyltransferase family.
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•Crystal structure of the conserved heteropentameric COMPASS catalytic core at 3.0 Å•Swd1 uses its C-terminal tail to form an inter-subunit regulatory pocket with Set1•Swd3 stimulates Set1 activity through the inter-subunit pocket via its SMART motif•A doorstop mechanism dictates substrate specificity of SET1/MLL methyltransferases
The crystal structure of the yeast COMPASS histone methyltransferase catalytic module reveals a doorstop-style mechanism dictating substrate selectivity.
There is conflicting evidence on the protective role of breastfeeding in relation to the development of allergic sensitisation and allergic disease. Studies vary in methodology and definition of ...outcomes, which lead to considerable heterogeneity. Human milk composition varies both within and between individuals, which may partially explain conflicting data. It is known that human milk composition is very complex and contains variable levels of immune active molecules, oligosaccharides, metabolites, vitamins and other nutrients and microbial content. Existing evidence suggests that modulation of human breast milk composition has potential for preventing allergic diseases in early life. In this review, we discuss associations between breastfeeding/human milk composition and allergy development.
Abstract
Cleavage stimulation factor (CstF) is a highly conserved protein complex composed of three subunits that recognizes G/U-rich sequences downstream of the polyadenylation signal of eukaryotic ...mRNAs. While CstF has been identified over 25 years ago, the architecture and contribution of each subunit to RNA recognition have not been fully understood. In this study, we provide a structural basis for the recruitment of CstF-50 to CstF via interaction with CstF-77 and establish that the hexameric assembly of CstF creates a high affinity platform to target various G/U-rich sequences. We further demonstrate that CstF-77 boosts the affinity of the CstF-64 RRM to the RNA targets and CstF-50 fine tunes the ability of the complex to recognize G/U sequences of certain lengths and content.
To date, there have been 6 cases of egg FPIES.1,4-6 The patients in these cases all had negative SPT responses, specific IgE (sIgE) levels, or both to egg, and only 1 case mentioned FPIES to baked ...egg.1 Atypical cases of FPIES with positive skin test results, sIgE levels to the triggering food, or both have been described, although unlike in 2 of our cases, the skin test results or sIgE levels were small or of low titer.2 Only 1 other child in our cohort had a positive SPT response to the triggering food (ie, a small response 3.5 mm to cow's milk). Patient 1 Patient 2 Patient 3 Patient 4 Sex Female Male Male Male Age at initial FPIES to egg (mo) 6 9 48 6 Age at which FPIES was diagnosed (mo) 14 15 54 15 Atopic disease at initial presentation Eczema IgE cow's milk allergy Nil Nil Description of episodes (age reaction, symptoms, formulation of egg) Episode 1 (6 mo) Whole egg V, L Episode 1 (8 mo) Baked egg V, L, D Multiple episodes (12x) V, L, and bloody diarrhea to baked and cooked egg Episode 1 (6 mo) Whole egg V, L
Maternal immune dysregulation seems to affect fetal or postnatal immune development. Preeclampsia is a pregnancy-associated disorder with an immune basis and is linked to atopic disorders in ...offspring. Here we show reduction of fetal thymic size, altered thymic architecture and reduced fetal thymic regulatory T (Treg) cell output in preeclamptic pregnancies, which persists up to 4 years of age in human offspring. In germ-free mice, fetal thymic CD4
T cell and Treg cell development are compromised, but rescued by maternal supplementation with the intestinal bacterial metabolite short chain fatty acid (SCFA) acetate, which induces upregulation of the autoimmune regulator (AIRE), known to contribute to Treg cell generation. In our human cohorts, low maternal serum acetate is associated with subsequent preeclampsia, and correlates with serum acetate in the fetus. These findings suggest a potential role of acetate in the pathogenesis of preeclampsia and immune development in offspring.
An efficient total chemical synthesis of site-specifically sumoylated histone H4 was undertaken to generate homogenously modified mononucleosomes. These were tested as substrates in biochemical ...assays with the histone H2B-specific ubiquitin ligases Rad6 and Bre1, which revealed the strong inhibition of H2B ubiquitylation by SUMO. This novel negative biochemical crosstalk between SUMO and ubiquitin was also confirmed to exist in human cells.
An efficient total chemical synthesis of site-specifically sumoylated histone H4 revealed its negative biochemical crosstalk with histone H2B ubiquitylation
in vitro
and in human cells.
The global disruption of the COVID‐19 pandemic has impacted the life of every child either directly or indirectly. This review explores the pathophysiology, immune response, clinical presentation and ...treatment of COVID‐19 in children, summarising the most up‐to‐date data including recent developments regarding variants of concern. The acute infection with SARS‐CoV‐2 is generally mild in children, whilst the post‐infectious manifestations, including paediatric inflammatory multisystem syndrome temporally associated with SARS‐CoV‐2 (PIMS‐TS) and ‘long COVID’ in children, are more complex. Given that most research on COVID‐19 has focused on adult cohorts and that clinical manifestations, treatment availability and impacts differ markedly in children, research that specifically examines COVID‐19 in children needs to be prioritised.
As the SARS-CoV-2 pandemic unfolds across the globe, consistent themes are emerging with regard to aspects of SARS-CoV-2 infection and its associated disease entities in children. Overall, children ...appear to be less frequently infected by, and affected by, SARS-CoV-2 virus and the clinical disease COVID-19. Large epidemiological studies have revealed children represent less than 2% of the total confirmed COVID-19 cases, of whom the majority experience minimal or mild disease that do not require hospitalisation. Children do not appear to be major drivers of SARS-CoV-2 transmission, with minimal secondary virus transmission demonstrated within families, schools and community settings. There are several postulated theories regarding the relatively low SARS-CoV-2 morbidity and mortality seen in children, which largely relate to differences in immune responses compared to adults, as well as differences in angiotensin converting enzyme 2 distribution that potentially limits viral entry and subsequent inflammation, hypoxia and tissue injury. The recent emergence of a multisystem inflammatory syndrome bearing temporal and serological plausibility for an immune-mediated SARS-CoV-2-related disease entity is currently under investigation. This article summarises the current available data regarding SARS-CoV-2 and the paediatric population, including the spectrum of disease in children, the role of children in virus transmission, and host-virus factors that underpin the unique aspects of SARS-CoV-2 pathogenicity in children.
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