Polycomb repressive complex 2 (PRC2) has oncogenic and tumor-suppressive roles in cancer. There is clinical success of targeting this complex in PRC2-dependent cancers, but an unmet therapeutic need ...exists in PRC2-loss cancer. PRC2-inactivating mutations are a hallmark feature of high-grade malignant peripheral nerve sheath tumor (MPNST), an aggressive sarcoma with poor prognosis and no effective targeted therapy. Through RNAi screening in MPNST, we found that PRC2 inactivation increases sensitivity to genetic or small-molecule inhibition of DNA methyltransferase 1 (DNMT1), which results in enhanced cytotoxicity and antitumor response. Mechanistically, PRC2 inactivation amplifies DNMT inhibitor-mediated expression of retrotransposons, subsequent viral mimicry response, and robust cell death in part through a protein kinase R (PKR)-dependent double-stranded RNA sensor. Collectively, our observations posit DNA methylation as a safeguard against antitumorigenic cell-fate decisions in PRC2-loss cancer to promote cancer pathogenesis, which can be therapeutically exploited by DNMT1-targeted therapy.
PRC2 inactivation drives oncogenesis in various cancers, but therapeutically targeting PRC2 loss has remained challenging. Here we show that PRC2-inactivating mutations set up a tumor context-specific liability for therapeutic intervention via DNMT1 inhibitors, which leads to innate immune signaling mediated by sensing of derepressed retrotransposons and accompanied by enhanced cytotoxicity. See related commentary by Guil and Esteller, p. 2020. This article is highlighted in the In This Issue feature, p. 2007.
Oxidative stress and inflammation are crucial factors contributing to the occurrence and development of vascular dementia (VD). In a previous study, we demonstrated that brozopine (BZP) is an ...anti-ischemic drug. In this study, a model of VD in rats with modified permanent bilateral common carotid artery occlusion (2-VO) was established in vivo , a model of cellular excitotoxicity/oxidative stress was established via L-glutamate-induced PC12 cell injury, a model of neuroinflammation was established in LPS-induced BV2 cells in vitro , and the ameliorative effect of BZP on cognitive impairment was assessed. BZP treatment improved memory deficit in VD rats through inhibiting Ca 2+ overload and the levels of oxidative stress, ferroptosis, and inflammatory markers (IL-1β, IL-6, and COX-2) in different brain regions. Additionally, we found that the levels of inflammatory markers in the plasma were also reduced in the VD rats. BZP was further found to have antioxidative stress, antiferroptosis (ferroptosis markers: GPX4, P53, and ACSL4), and antineuroinflammatory effects in PC12 and BV2 cells. Its mechanisms of action were found to be related to the activation of the Nrf2/TLR4/NF-κB pathway; the protective effect of BZP was partially inhibited after using Nrf2-specific inhibitors. Thus, BZP has therapeutic properties for the potential mitigation of cognitive impairment.
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CASK is a scaffold protein that functions in trafficking and targeting of synaptic proteins in the central nervous system. Emerging literature suggests that CASK localizes inside ...nucleus and might regulate transcription by interacting with TBR1, a transcription factor essential for brain development. However, these regulatory mechanisms are not well established. We hypothesize that CASK is involved in neuronal activity‐regulated transcription. To test our hypothesis, we used primary cultures of mouse cortical neurons stimulated with KCL depolarization buffer, which is known to activate a robust CREB‐dependent gene expression program and to induce the activation of distal enhancer elements. To measure gene expression genome‐wide, we performed RNAseq in unstimulated or KCL‐treated neurons after knock‐down of CASK expression using specific shRNA. Our results show that CASK knock‐down strongly reduces the number of genes that are regulated by depolarization. These results indicate that CASK is required for gene expression regulation in neuronal cells. To gain further insights in the mechanisms by which CASK regulate transcription, we used RNA in situ hybridization (RNAscope) to test the hypothesis that CASK is not only required for the transcription of coding genes, but also of non‐coding RNAs, termed ‘enhancer RNAs (eRNAs), in proximity of KCL‐regulated genes. We showed that RNAscope is a valid method to measure eRNAs induction after KCl treatment. Ongoing experiments in the lab are assessing the effect of CASK knock‐down on eRNA transcription. Interestingly, we observed by immunoprecipitation that nuclear CASK dimerizes, and that the stability of this homodimer is dependent on the presence of RNA. Finally, we used biochemical fractionation to study CASK localization in the nucleus in both mouse neuronal cultures and brain tissues. These results shed light on how CASK functions in neurons. This study is relevant to human disease because mutations in CASK gene are linked to microcephaly and X‐linked intellectual disability.
Support or Funding Information
This project has been supported by CABRI Undergraduate Research Fellowship
Co3O4/In2O3 nanocomposites were prepared via a microwave-hydrothermal method and directly used as photoanodes for the photoelectrocatalytic (PEC) process to reduce Cr(VI). The as-prepared ...Co3O4/In2O3 composites show a rod-like structure, which is composed of nanoparticles. The PEC experiments indicated that after 120 min of irradiation with 0.7 V bias voltage and visible light, the Cr(VI) reduction efficiency of Co3O4/In2O3 composites in aqueous solution was 100%, which was superior to the samples prepared by other methods. Moreover, the Co3O4/In2O3 composite still had a high catalytic activity after five runs of PEC experiments. Elimination experiments demonstrate that photo-generated electrons (e–) performed a key role in the catalytic reduction of Cr(VI). The significantly improved PEC performance can be attributed to the bias voltage and the p-n heterojunction formed between Co3O4 and In2O3. Therefore, Co3O4/In2O3 nanocomposites have a considerable potential for the PEC reduction of Cr(VI).
Inflammation is essential to the disruption of tissue homeostasis and can destabilize the identity of lineage-committed epithelial cells. Here, we employ lineage-traced mouse models, single-cell ...transcriptomic and chromatin analyses, and CUT&TAG to identify an epigenetic memory of inflammatory injury in the pancreatic acinar cell compartment. Despite resolution of pancreatitis, our data show that acinar cells fail to return to their molecular baseline, with retention of elevated chromatin accessibility and H3K4me1 at metaplasia genes, such that memory represents an incomplete cell fate decision. In vivo, we find this epigenetic memory controls lineage plasticity, with diminished metaplasia in response to a second insult but increased tumorigenesis with an oncogenic Kras mutation. The lowered threshold for oncogenic transformation, in turn, can be restored by blockade of MAPK signaling. Together, we define the chromatin dynamics, molecular encoding, and recall of a prolonged epigenetic memory of inflammatory injury that impacts future responses but remains reversible.
The ability to rapidly change gene expression patterns is essential for differentiation, development, and functioning of the brain. Throughout development, or in response to environmental stimuli, ...gene expression patterns are tightly regulated by the dynamic interplay between transcription activators and repressors. Nuclear receptor corepressor 1 (NCoR1) and silencing mediator for retinoid or thyroid‐hormone receptors (SMRT) are the best characterized transcriptional co‐repressors from a molecular point of view. They mediate epigenetic silencing of gene expression in a wide range of developmental and homeostatic processes in many tissues, including the brain. For instance, NCoR1 and SMRT regulate neuronal stem cell proliferation and differentiation during brain development and they have been implicated in learning and memory. However, we still have a limited understanding of their regional and cell type‐specific expression in the brain. In this study, we used fluorescent immunohistochemistry to map their expression patterns throughout the adult mouse brain. Our findings reveal that NCoR1 and SMRT share an overall neuroanatomical distribution, and are detected in both excitatory and inhibitory neurons. However, we observed striking differences in their cell type‐specific expression in glial cells. Specifically, all oligodendrocytes express NCoR1, but only a subset express SMRT. In addition, NCoR1, but not SMRT, was detected in a subset of astrocytes and in the microglia. These novel observations are corroborated by single cell transcriptomics and emphasize how NCoR1 and SMRT may contribute to distinct biological functions, suggesting an exclusive role of NCoR1 in innate immune responses in the brain.
Schematic representation of NCoR1 and SMRT distribution in neuronal and non‐neuronal cell types. Five major types of brain cells (glutamatergic and GABAergic neurons, astrocytes, oligodendrocytes, and microglia) are depicted within a representative coronal slice of the mouse brain. Both NCor1 and SMRT broadly localize within the nuclei of most neuronal cells. However, a diverse pattern of expression is detected in non‐neuronal cells. While NCoR1 is expressed in a small fraction of astrocytes, SMRT is not expressed in GFAP+ astrocytes or in Iba1+ microglia.
Abstract
Polycomb Repressive Complex 2 (PRC2) establishes and maintains di- and tri-methylation at histone 3 at lysine 27 (H3K27me2/3) in the genome and plays oncogenic and tumor suppressor roles in ...context-dependent cancer pathogenesis. While there is clinical success of therapeutically targeting PRC2 core component, EZH2, in PRC2-dependent cancers (e.g., follicular lymphoma, epithelioid sarcoma), it remains an unmet therapeutic bottleneck in PRC2-inactivated cancer. Biallelic inactivating mutations in PRC2 core components are a hallmark feature of high-grade malignant peripheral nerve sheath tumor (MPNST), an aggressive subtype of sarcoma with poor prognosis and no effective targeted therapeutics. Using a custom RNAi-based drop out screen, we observed that PRC2-inactivation is synthetic lethal with DNA methyltransferase 1 (DNMT1) downregulation; we further observed that small molecule DNMT inhibitors (DNMTis) resulted in enhanced cytotoxicity and anti-tumor responses in PRC2-loss cancer context in vitro and in vivo. Mechanistically, DNMTi-mediated de-repression of retrotransposons (e.g., endogenous retroviral elements) and gene targets is partly restricted by PRC2, which potentially contributes to limited therapeutic activity in PRC2-wild-type (wt) cancer context. In contrast, DNMTi treatment synergizes with PRC2 inactivation and cooperatively amplifies the expression of retrotransposons, and subsequent viral mimicry response that promotes robust cell death in part through PKR-dependent double stranded-RNA (dsRNA) sensing. Collectively, our observations posit DNA methylation as a safeguard against anti-tumorigenic cell fate decisions in the context of PRC2-inactivation to promote cancer pathogenesis, identify DNMT1-targeted therapy as novel therapeutic strategy for PRC2-inactivated MPNST, and merit further preclinical and clinical investigation of this strategy in other PRC2-inactivated cancers.
Citation Format: Ping Chi, Amish J. Patel, Sarah Warda, Jesper L.V. Maag, Rohan Misra, Miguel A. Miranda-Román, Mohini R. Pachai, Cindy J. Lee, Dan Li, Naitao Wang, Gabriella Bayshtok, Eve Fishinevich, Yinuo Meng, Elissa W.P. Wong, Juan Yan, Emily Giff, Jonathan Fletcher, Joseph M. Scandura, Richard Koche, Jacob L. Glass, Cristina R. Antonescu, Deyou Zheng, Yu Chen. PRC2 inactivating mutations amplify cell death in response to DNMT1-targeted therapy through enhanced viral mimicry in malignant peripheral nerve sheath tumor abstract. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr PR005.
To effectively control the dust generated by coal mining operations, a new type of cyclonic pneumatic mist curtain dust control device was developed. Using CFD software, numerical simulations were ...conducted on the internal airflow velocity field, the exit velocity of the cyclonic pneumatic mist curtain, and the mist droplet particle field of the curtain. Experiments were carried out to measure the spray coverage, droplet size, and the dust control performance of the model device. The results indicate that when the water pump supply pressure is 8 MPa, the fan supply wind speed is 12 m/s, and the nozzle installation angle is 75 degrees, the cyclonic pneumatic mist curtain dust control device model operates under optimal conditions. The effective coverage of the cyclonic mist curtain is 380 × 3300 mm, fully suppressing dust generation on one side of the curtain. An optimal dust removal distance of about 90 cm was determined. After installing the cyclonic pneumatic mist curtain dust control device, the average dust reduction efficiency for respirable dust reached 91.07%, and the overall dust reduction efficiency achieved 93.34%.
The power sector is the main contributor to climate change and atmospheric pollution, and reducing the emissions from the power sector is essential for achieving sustainable development. However, few ...studies have accounted for the emissions from various power-generation technologies. In this paper, a high-resolution inventory of power plants with more than 6 MW accounting for 93% of the national power generation in China is established for the first time. Based on this inventory, the CO2, NOx and SO2 emissions of China's hard coal power, natural gas power, hydropower, wind power, photovoltaic power, biomass power and nuclear power are calculated by using the life cycle assessment method, and their spatial distributions in 2014 are further analyzed. The results show that China's power plants emitted 3.44 E+09 t CO2, 8.56 E+06 t NOx, and 1.19 E+07 t SO2, and the uncertainties were (−18.66%, +19.14%), (−67.10%, +66.41%) and (−88.69%, +87.61%) in 2014, respectively. Renewable-energy power plants accounted for approximately 15% of the national power generation but only contributed less than 1% of the total emissions. Meanwhile, in China's eastern cities, renewable-energy power accounts for the lowest proportion of the total installed capacity. In addition, both the emission amount and intensity were significantly higher in eastern cities than central and western cities. This study will help improve research on the emissions of all power-generation technologies in China and help achieve a comprehensive and systematic emissions reduction strategy.
•A high-resolution inventory of China's power plants is established.•The emissions of CO2, NOx and SO2 are considered.•The emissions from renewable power generation in China are calculated.•The spatial distribution of China's power plants' emissions is analyzed.•Comprehensive strategies for regional electricity development are proposed.
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