Loss of MHC class I (MHC-I) antigen presentation in cancer cells can elicit immunotherapy resistance. A genome-wide CRISPR/Cas9 screen identified an evolutionarily conserved function of polycomb ...repressive complex 2 (PRC2) that mediates coordinated transcriptional silencing of the MHC-I antigen processing pathway (MHC-I APP), promoting evasion of T cell-mediated immunity. MHC-I APP gene promoters in MHC-I low cancers harbor bivalent activating H3K4me3 and repressive H3K27me3 histone modifications, silencing basal MHC-I expression and restricting cytokine-induced upregulation. Bivalent chromatin at MHC-I APP genes is a normal developmental process active in embryonic stem cells and maintained during neural progenitor differentiation. This physiological MHC-I silencing highlights a conserved mechanism by which cancers arising from these primitive tissues exploit PRC2 activity to enable immune evasion.
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•PRC2 maintains bivalency at MHC-I antigen-processing genes silencing MHC-I expression•Cancer cells co-opt this conserved, lineage-specific PRC2 function to evade T cells•Pharmacological inhibition of PRC2 in MHC-I low cancers restores anti-tumor immunity•Immunotherapy resistance may arise via non-genomic routes that exploit PRC2 activity
Burr et al. show that cancer cells co-opt PRC2 to evade immune surveillance. PRC2 maintains bivalency at the promoters of MHC-I antigen-processing pathway (MHC-I APP) genes to repress their basal and cytokine-activated expression. Inhibition of PRC2 restores the MHC-I APP and T cell-mediated anti-tumor immunity.
ABSTRACT Although there has been much progress in understanding how galaxies evolve, we still do not understand how and when they stop forming stars and become quiescent. We address this by applying ...our galaxy spectral energy distribution models, which incorporate physically motivated star formation histories (SFHs) from cosmological simulations, to a sample of quiescent galaxies at . A total of 845 quiescent galaxies with multi-band photometry spanning rest-frame ultraviolet through near-infrared wavelengths are selected from the Cosmic Assembly Near-IR Deep Extragalactic Legacy Survey (CANDELS) data set. We compute median SFHs of these galaxies in bins of stellar mass and redshift. At all redshifts and stellar masses, the median SFHs rise, reach a peak, and then decline to reach quiescence. At high redshift, we find that the rise and decline are fast, as expected, because the universe is young. At low redshift, the duration of these phases depends strongly on stellar mass. Low-mass galaxies ( ) grow on average slowly, take a long time to reach their peak of star formation ( Gyr), and then the declining phase is fast ( Gyr). Conversely, high-mass galaxies ( ) grow on average fast ( Gyr), and, after reaching their peak, decrease the star formation slowly ( ). These findings are consistent with galaxy stellar mass being a driving factor in determining how evolved galaxies are, with high-mass galaxies being the most evolved at any time (i.e., downsizing). The different durations we observe in the declining phases also suggest that low- and high-mass galaxies experience different quenching mechanisms, which operate on different timescales.
We introduce multi-trait analysis of GWAS (MTAG), a method for joint analysis of summary statistics from genome-wide association studies (GWAS) of different traits, possibly from overlapping samples. ...We apply MTAG to summary statistics for depressive symptoms (N
= 354,862), neuroticism (N = 168,105), and subjective well-being (N = 388,538). As compared to the 32, 9, and 13 genome-wide significant loci identified in the single-trait GWAS (most of which are themselves novel), MTAG increases the number of associated loci to 64, 37, and 49, respectively. Moreover, association statistics from MTAG yield more informative bioinformatics analyses and increase the variance explained by polygenic scores by approximately 25%, matching theoretical expectations.
Iron storage proteins are essential for cellular iron homeostasis and redox balance. Ferritin proteins are the major storage units for bioavailable forms of iron. Some organisms lack ferritins, and ...it is not known how they store iron. Encapsulins, a class of protein-based organelles, have recently been implicated in microbial iron and redox metabolism. Here, we report the structural and mechanistic characterization of a 42 nm two-component encapsulin-based iron storage compartment from
. Using cryo-electron microscopy and x-ray crystallography, we reveal the assembly principles of a thermostable T = 4 shell topology and its catalytic ferroxidase cargo and show interactions underlying cargo-shell co-assembly. This compartment has an exceptionally large iron storage capacity storing over 23,000 iron atoms. Our results reveal a new approach for survival in diverse habitats with limited or fluctuating iron availability via an iron storage system able to store 10 to 20 times more iron than ferritin.
Cardiac macrophages represent a heterogeneous cell population with distinct origins, dynamics, and functions. Recent studies have revealed that C-C Chemokine Receptor 2 positive (CCR2+) macrophages ...derived from infiltrating monocytes regulate myocardial inflammation and heart failure pathogenesis. Comparatively little is known about the functions of tissue resident (CCR2−) macrophages. Herein, we identified an essential role for CCR2− macrophages in the chronically failing heart. Depletion of CCR2− macrophages in mice with dilated cardiomyopathy accelerated mortality and impaired ventricular remodeling and coronary angiogenesis, adaptive changes necessary to maintain cardiac output in the setting of reduced cardiac contractility. Mechanistically, CCR2− macrophages interacted with neighboring cardiomyocytes via focal adhesion complexes and were activated in response to mechanical stretch through a transient receptor potential vanilloid 4 (TRPV4)-dependent pathway that controlled growth factor expression. These findings establish a role for tissue-resident macrophages in adaptive cardiac remodeling and implicate mechanical sensing in cardiac macrophage activation.
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•The failing heart contains heterogeneous subsets of resident and recruited macrophages•Resident cardiac macrophages promote adaptation and survival of the failing heart•Resident cardiac macrophages interact with cardiomyocytes via focal adhesion complexes•Resident cardiac macrophages sense mechanical stretch through TRPV4 channels
Resident cardiac macrophages are key regulators of heart development and homeostasis; however, the role of these cells during disease is presently unclear. Wong, Mohan, Kopecky, et al. reveal that resident cardiac macrophages orchestrate adaptive remodeling and survival of the failing heart by sensing mechanical stimuli through a TRPV4 dependent mechanism.
Circadian clocks generate rhythms of arousal, but the underlying molecular and cellular mechanisms remain unclear. In Drosophila, the clock output molecule WIDE AWAKE (WAKE) labels rhythmic neural ...networks and cyclically regulates sleep and arousal. Here, we show, in a male mouse model, that mWAKE/ANKFN1 labels a subpopulation of dorsomedial hypothalamus (DMH) neurons involved in rhythmic arousal and acts in the DMH to reduce arousal at night. In vivo Ca
imaging reveals elevated DMH
activity during wakefulness and rapid eye movement (REM) sleep, while patch-clamp recordings show that DMH
neurons fire more frequently at night. Chemogenetic manipulations demonstrate that DMH
neurons are necessary and sufficient for arousal. Single-cell profiling coupled with optogenetic activation experiments suggest that GABAergic DMH
neurons promote arousal. Surprisingly, our data suggest that mWAKE acts as a clock-dependent brake on arousal during the night, when mice are normally active. mWAKE levels peak at night under clock control, and loss of mWAKE leads to hyperarousal and greater DMH
neuronal excitability specifically at night. These results suggest that the clock does not solely promote arousal during an animal's active period, but instead uses opposing processes to produce appropriate levels of arousal in a time-dependent manner.
Microorganisms drive soil carbon mineralization and changes in their activity with increased temperature could feedback to climate change. Variation in microbial biodiversity and the temperature ...sensitivities (Q
) of individual taxa may explain differences in the Q
of soil respiration, a possibility not previously examined due to methodological limitations. Here, we show phylogenetic and taxonomic variation in the Q
of growth (5-35 °C) among soil bacteria from four sites, one from each of Arctic, boreal, temperate, and tropical biomes. Differences in the temperature sensitivities of taxa and the taxonomic composition of communities determined community-assembled bacterial growth Q
, which was strongly predictive of soil respiration Q
within and across biomes. Our results suggest community-assembled traits of microbial taxa may enable enhanced prediction of carbon cycling feedbacks to climate change in ecosystems across the globe.
•Extracellular vesicles (EVs) are potent vehicles of intercellular communication.•EVs can transport pathological cargo that contributes to disease.•One pathway of EV biogenesis is dependent upon ...ceramides generated by nSMase2.•Inhibition of nSMase2 shows promise in treating diseases that propagate via EVs.•Potent and selective nSMase2 inhibitors have recently been discovered.
Extracellular vesicles (EVs) are indispensable mediators of intercellular communication, but they can also assume a nefarious role by ferrying pathological cargo that contributes to neurological, oncological, inflammatory, and infectious diseases. The canonical pathway for generating EVs involves the endosomal sorting complexes required for transport (ESCRT) machinery, but an alternative pathway is induced by the enrichment of lipid membrane ceramides generated by neutral sphingomyelinase 2 (nSMase2). Inhibition of nSMase2 has become an attractive therapeutic strategy for inhibiting EV biogenesis, and a growing number of small-molecule nSMase2 inhibitors have shown promising therapeutic activity in preclinical disease models. This review outlines the function of EVs, their potential role in disease, the discovery and efficacy of nSMase2 inhibitors, and the path to translate these findings into therapeutics.
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