FBXO44 promotes DNA replication-coupled repetitive element silencing in cancer cells

Shen, Jia; Qiu, Zhixin; Wu, Qiulian; Finlay, Darren; Garcia, Guillermina; Sun, Dahui; Rantala, Juha; Barshop, William D.; Hope, Jennifer L.; Gimple, Ryan C.; Sangfelt, Olle; Bradley, Linda M.; Wohlschlegel, James A.; Rich, Jeremy; Spruck, Charles

doi:10.1016/j.cell.2020.11.042

Cited by 64 publications

(53 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We propose that our model is applicable beyond infection. Natural TE expression correlates with better anti-tumor T cell responses (93) and the notion that enhanced TE expression drives an inflammatory response that is correlated with better clinical outcome, particularly after immunotherapy, is supported by studies that enhanced TE expression and the ensuing inflammatory responses either by small molecule inhibitors of DNA methylation or genetic ablation of epigenetic regulators (9,(94)(95)(96). Likewise, disruption of histone methylation by ablation of SETDB1 led to TE dsRNA sensing and IFN-I responses in different cell lines including acute myeloid leukemia (10) and non-small-cell lung cancer (11).…”

Section: Cancermentioning

confidence: 98%

Induction of transposable element expression is central to innate sensing

Rookhuizen

Bonté

et al. 2021

Preprint

View full text Add to dashboard Cite

Evidence indicates that transposable elements (TEs) stimulate innate sensing pathways in various pathologies but it is not clear whether they are sensed during normal physiological responses. Here we show that, during activation with an exogenous pathogen associated molecular pattern (PAMP), dendritic cells (DCs) epigenetically remodel heterochromatin at TEs by depleting the methyltransferase Suv39h1 and reducing histone-3 lysine-9 trimethylation (H3K9me3). TLR4 signaling activates TE expression to enhance innate responses through the DNA sensor cGAS. Cytosolic cGAS-bound DNA comprised LINE1 TEs as the predominant endogenous ligands. Concordantly, LINE1 inhibition attenuated the type-I IFN response to LPS and rescued influenza virus infection. We propose that in healthy cells, exogenous PAMPs epigenetically activate self-derived PAMPs (LINE1) that engage cGAS to enhance responses. These data explain why pathogens employ redundant and broad innate immune countermeasures, to suppress activation of host PAMPs and illustrate a hitherto unappreciated role for host genome-derived PAMPs in response to pathogens.

show abstract

Section: Cancermentioning

confidence: 98%

Induction of transposable element expression is central to innate sensing

Rookhuizen

Bonté

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Recent evidence indicates that disease severity predominantly depends on host factors [ 5 – 10 ], supporting the need to better resolve individual responses at the molecular level. We and others have recently described the multi-omic profile of COVID-19 patients in association with disease severity [ 10 – 12 ]. Analysis of mRNA sequencing from circulating leukocytes identified multiple expressed genes associated with worse outcomes [ 10 , 11 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Blood DNA methylation and COVID-19 outcomes

et al. 2021

View full text Add to dashboard Cite

Background There are no prior reports that compare differentially methylated regions of DNA in blood samples from COVID-19 patients to samples collected before the SARS-CoV-2 pandemic using a shared epigenotyping platform. We performed a genome-wide analysis of circulating blood DNA CpG methylation using the Infinium Human MethylationEPIC BeadChip on 124 blood samples from hospitalized COVID-19-positive and COVID-19-negative patients and compared these data with previously reported data from 39 healthy individuals collected before the pandemic. Prospective outcome measures such as COVID-19-GRAM risk-score and mortality were combined with methylation data. Results Global mean methylation levels did not differ between COVID-19 patients and healthy pre-pandemic controls. About 75% of acute illness-associated differentially methylated regions were located near gene promoter regions and were hypo-methylated in comparison with healthy pre-pandemic controls. Gene ontology analyses revealed terms associated with the immune response to viral infections and leukocyte activation; and disease ontology analyses revealed a predominance of autoimmune disorders. Among COVID-19-positive patients, worse outcomes were associated with a prevailing hyper-methylated status. Recursive feature elimination identified 77 differentially methylated positions predictive of COVID-19 severity measured by the GRAM-risk score. Conclusion Our data contribute to the awareness that DNA methylation may influence the expression of genes that regulate COVID-19 progression and represent a targetable process in that setting.

show abstract

“…Recent metabolomics studies of human plasma have identified the kynurenine pathway, acylcarnitines and acyl-GPCs as prognostic markers of Covid-19 disease severity 47 – 50 . A consistent message is that metabolic dysfunction occurs in respiratory distress.…”

Section: Discussionmentioning

confidence: 99%

A metabolomic endotype of bioenergetic dysfunction predicts mortality in critically ill patients with acute respiratory failure

Migaud

Flores

Thompson

et al. 2021

Sci Rep

View full text Add to dashboard Cite

Acute respiratory failure (ARF) requiring mechanical ventilation, a complicating factor in sepsis and other disorders, is associated with high morbidity and mortality. Despite its severity and prevalence, treatment options are limited. In light of accumulating evidence that mitochondrial abnormalities are common in ARF, here we applied broad spectrum quantitative and semiquantitative metabolomic analyses of serum from ARF patients to detect bioenergetic dysfunction and determine its association with survival. Plasma samples from surviving and non-surviving patients (N = 15/group) were taken at day 1 and day 3 after admission to the medical intensive care unit and, in survivors, at hospital discharge. Significant differences between survivors and non-survivors (ANOVA, 5% FDR) include bioenergetically relevant intermediates of redox cofactors nicotinamide adenine dinucleotide (NAD) and NAD phosphate (NADP), increased acyl-carnitines, bile acids, and decreased acyl-glycerophosphocholines. Many metabolites associated with poor outcomes are substrates of NAD(P)-dependent enzymatic processes, while alterations in NAD cofactors rely on bioavailability of dietary B-vitamins thiamine, riboflavin and pyridoxine. Changes in the efficiency of the nicotinamide-derived cofactors’ biosynthetic pathways also associate with alterations in glutathione-dependent drug metabolism characterized by substantial differences observed in the acetaminophen metabolome. Based on these findings, a four-feature model developed with semi-quantitative and quantitative metabolomic results predicted patient outcomes with high accuracy (AUROC = 0.91). Collectively, this metabolomic endotype points to a close association between mitochondrial and bioenergetic dysfunction and mortality in human ARF, thus pointing to new pharmacologic targets to reduce mortality in this condition.

show abstract

FBXO44 promotes DNA replication-coupled repetitive element silencing in cancer cells

Cited by 64 publications

References 74 publications

Induction of transposable element expression is central to innate sensing

Induction of transposable element expression is central to innate sensing

Blood DNA methylation and COVID-19 outcomes

A metabolomic endotype of bioenergetic dysfunction predicts mortality in critically ill patients with acute respiratory failure

Contact Info

Product

Resources

About