The molecular basis of signal-dependent transcriptional activation has been extensively studied in macrophage polarization, but our understanding remains limited regarding the molecular determinants ...of repression. Here we show that IL-4-activated STAT6 transcription factor is required for the direct transcriptional repression of a large number of genes during in vitro and in vivo alternative macrophage polarization. Repression results in decreased lineage-determining transcription factor, p300, and RNA polymerase II binding followed by reduced enhancer RNA expression, H3K27 acetylation, and chromatin accessibility. The repressor function of STAT6 is HDAC3 dependent on a subset of IL-4-repressed genes. In addition, STAT6-repressed enhancers show extensive overlap with the NF-κB p65 cistrome and exhibit decreased responsiveness to lipopolysaccharide after IL-4 stimulus on a subset of genes. As a consequence, macrophages exhibit diminished inflammasome activation, decreased IL-1β production, and pyroptosis. Thus, the IL-4-STAT6 signaling pathway establishes an alternative polarization-specific epigenenomic signature resulting in dampened macrophage responsiveness to inflammatory stimuli.
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•IL-4-activated STAT6 acts as a transcriptional repressor in macrophages•IL-4-STAT6-repressed enhancers associate with reduced LDTF and p300 binding•Inflammatory responsiveness of the IL-4-repressed enhancers is attenuated•IL-4 limits the LPS-induced inflammasome activation, IL-1β production, and pyroptosis
The molecular bases of repressive transcriptional mechanisms contributing to macrophage polarization are not well understood. Czimmerer et al. show that in alternatively polarized macrophages, IL-4-activated STAT6 represses a large set of enhancers modulating the transcriptional program. STAT6-repressed enhancers are characterized by reduced chromatin accessibility, eRNA expression, LDTF, and p300 binding. IL-4-STAT6-mediated repression limits the inflammatory responsiveness including inflammasome activation, IL-1β production, and pyroptosis. Thus, the IL4-STAT6 pathway establishes an epigenomic signature to selectively repress the macrophage inflammation program.
While admixed populations offer a unique opportunity to detect selection, the admixture in most of the studied populations occurred too recently to produce conclusive signals. By contrast, Malagasy ...populations originate from admixture between Asian and African populations that occurred ~27 generations ago, providing power to detect selection. We analyze local ancestry across the genomes of 700 Malagasy and identify a strong signal of recent positive selection, with an estimated selection coefficient >0.2. The selection is for African ancestry and affects 25% of chromosome 1, including the Duffy blood group gene. The null allele at this gene provides resistance to Plasmodium vivax malaria, and previous studies have suggested positive selection for this allele in the Malagasy population. This selection event also influences numerous other genes implicated in immunity, cardiovascular diseases, and asthma and decreases the Asian ancestry genome-wide by 10%, illustrating the role played by selection in recent human history.
Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are autosomal dominant neuromuscular diseases caused by microsatellite expansions and belong to the family of RNA-dominant disorders. Availability of ...cellular models in which the DM mutation is expressed within its natural context is essential to facilitate efforts to identify new therapeutic compounds. Here, we generated immortalized DM1 and DM2 human muscle cell lines that display nuclear RNA aggregates of expanded repeats, a hallmark of myotonic dystrophy. Selected clones of DM1 and DM2 immortalized myoblasts behave as parental primary myoblasts with a reduced fusion capacity of immortalized DM1 myoblasts when compared with control and DM2 cells. Alternative splicing defects were observed in differentiated DM1 muscle cell lines, but not in DM2 lines. Splicing alterations did not result from differentiation delay because similar changes were found in immortalized DM1 transdifferentiated fibroblasts in which myogenic differentiation has been forced by overexpression of MYOD1. As a proof-of-concept, we show that antisense approaches alleviate disease-associated defects, and an RNA-seq analysis confirmed that the vast majority of mis-spliced events in immortalized DM1 muscle cells were affected by antisense treatment, with half of them significantly rescued in treated DM1 cells. Immortalized DM1 muscle cell lines displaying characteristic disease-associated molecular features such as nuclear RNA aggregates and splicing defects can be used as robust readouts for the screening of therapeutic compounds. Therefore, immortalized DM1 and DM2 muscle cell lines represent new models and tools to investigate molecular pathophysiological mechanisms and evaluate the
effects of compounds on RNA toxicity associated with myotonic dystrophy mutations.
Malaria infection is a multifactorial disease partly modulated by host immuno-genetic factors. Recent evidence has demonstrated the importance of Interleukin-17 family proinflammatory cytokines and ...their genetic variants in host immunity. However, limited knowledge exists about their role in parasitic infections such as malaria. We aimed to investigate IL-17A serum levels in patients with severe and uncomplicated malaria and gene polymorphism's influence on the IL-17A serum levels. In this research, 125 severe (SM) and uncomplicated (UM) malaria patients and 48 free malaria controls were enrolled. IL-17A serum levels were measured with ELISA. PCR and DNA sequencing were used to assess host genetic polymorphisms in IL-17A. We performed a multivariate regression to estimate the impact of human IL-17A variants on IL-17A serum levels and malaria outcomes. Elevated serum IL-17A levels accompanied by increased parasitemia were found in SM patients compared to UM and controls (P < 0.0001). Also, the IL-17A levels were lower in SM patients who were deceased than in those who survived. In addition, the minor allele frequencies (MAF) of two IL-17A polymorphisms (rs3819024 and rs3748067) were more prevalent in SM patients than UM patients, indicating an essential role in SM. Interestingly, the heterozygous rs8193038 AG genotype was significantly associated with higher levels of IL-17A than the homozygous wild type (AA). According to our results, it can be concluded that the IL-17A gene rs8193038 polymorphism significantly affects IL-17A gene expression. Our results fill a gap in the implication of IL-17A gene polymorphisms on the cytokine level in a malaria cohort. IL-17A gene polymorphisms also may influence cytokine production in response to Plasmodium infections and may contribute to the hyperinflammatory responses during severe malaria outcomes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Motivation
It is more and more common to perform multi-omics analyses to explore the genome at diverse levels and not only at a single level. Through integrative statistical methods, ...multi-omics data have the power to reveal new biological processes, potential biomarkers and subgroups in a cohort. Matrix factorization (MF) is an unsupervised statistical method that allows a clustering of individuals, but also reveals relevant omics variables from the various blocks.
Results
Here, we present PIntMF (Penalized Integrative Matrix Factorization), an MF model with sparsity, positivity and equality constraints. To induce sparsity in the model, we used a classical Lasso penalization on variable and individual matrices. For the matrix of samples, sparsity helps in the clustering, while normalization (matching an equality constraint) of inferred coefficients is added to improve interpretation. Moreover, we added an automatic tuning of the sparsity parameters using the famous glmnet package. We also proposed three criteria to help the user to choose the number of latent variables. PIntMF was compared with other state-of-the-art integrative methods including feature selection techniques in both synthetic and real data. PIntMF succeeds in finding relevant clusters as well as variables in two types of simulated data (correlated and uncorrelated). Next, PIntMF was applied to two real datasets (Diet and cancer), and it revealed interpretable clusters linked to available clinical data. Our method outperforms the existing ones on two criteria (clustering and variable selection). We show that PIntMF is an easy, fast and powerful tool to extract patterns and cluster samples from multi-omics data.
Availability and implementation
An R package is available at https://github.com/mpierrejean/pintmf.
Supplementary information
Supplementary data are available at Bioinformatics online.
Treacher Collins syndrome (TCS) is a rare autosomal dominant mandibulofacial dysostosis, with a prevalence of 0.2–1/10,000. Features include bilateral and symmetrical malar and mandibular hypoplasia ...and facial abnormalities due to abnormal neural crest cell (NCC) migration and differentiation. To date, three genes have been identified: TCOF1, POLR1C, and POLR1D. Despite a large number of patients with a molecular diagnosis, some remain without a known genetic anomaly.
We performed exome sequencing for four individuals with TCS but who were negative for pathogenic variants in the known causative genes. The effect of the pathogenic variants was investigated in zebrafish.
We identified three novel pathogenic variants in POLR1B. Knockdown of polr1b in zebrafish induced an abnormal craniofacial phenotype mimicking TCS that was associated with altered ribosomal gene expression, massive p53-associated cellular apoptosis in the neuroepithelium, and reduced number of NCC derivatives.
Pathogenic variants in the RNA polymerase I subunit POLR1B might induce massive p53-dependent apoptosis in a restricted neuroepithelium area, altering NCC migration and causing cranioskeletal malformations. We identify POLR1B as a new causative gene responsible for a novel TCS syndrome (TCS4) and establish a novel experimental model in zebrafish to study POLR1B-related TCS.
IMPORTANCE: After an infection by SARS-CoV-2, many patients present with persistent physical symptoms that may impair their quality of life. Beliefs regarding the causes of these symptoms may ...influence their perception and promote maladaptive health behaviors. OBJECTIVE: To examine the associations of self-reported COVID-19 infection and SARS-CoV-2 serology test results with persistent physical symptoms (eg, fatigue, breathlessness, or impaired attention) in the general population during the COVID-19 pandemic. DESIGN, SETTING, AND PARTICIPANTS: Participants in this cross-sectional analysis were 26 823 individuals from the French population-based CONSTANCES cohort, included between 2012 and 2019, who took part in the nested SAPRIS and SAPRIS-SERO surveys. Between May and November 2020, an enzyme-linked immunosorbent assay was used to detect anti–SARS-CoV-2 antibodies. Between December 2020 and January 2021, the participants reported whether they believed they had experienced COVID-19 infection and had physical symptoms during the previous 4 weeks that had persisted for at least 8 weeks. Participants who reported having an initial COVID-19 infection only after completing the serology test were excluded. MAIN OUTCOMES AND MEASURES: Logistic regressions for each persistent symptom as the outcome were computed in models including both self-reported COVID-19 infection and serology test results and adjusting for age, sex, income, and educational level. RESULTS: Of 35 852 volunteers invited to participate in the study, 26 823 (74.8%) with complete data for serologic testing and self-reported infection were included in the present study (mean SD age, 49.4 12.9 years; 13 731 women 51.2%). Self-reported infection was positively associated with persistent physical symptoms, with odds ratios ranging from 1.44 (95% CI, 1.08-1.90) to 16.61 (95% CI, 10.30-26.77) except for hearing impairment (odds ratio, 1.38; 95% CI, 0.76-2.51), joint pain (odds ratio, 1.32; 95% CI, 0.98-1.80) and sleep problems (odds ratio, 1.12; 95% CI, 0.87-1.44). A serology test result positive for SARS-COV-2 was positively associated only with persistent anosmia (odds ratio, 2.59; 95% CI, 1.57-4.28), even when restricting the analyses to participants who attributed their symptoms to COVID-19 infection. Further adjusting for self-rated health or depressive symptoms yielded similar results. There was no significant interaction between belief and serology test results. CONCLUSIONS AND RELEVANCE: The findings of this cross-sectional analysis of a large, population-based French cohort suggest that persistent physical symptoms after COVID-19 infection may be associated more with the belief in having been infected with SARS-CoV-2 than with having laboratory-confirmed COVID-19 infection. Further research in this area should consider underlying mechanisms that may not be specific to the SARS-CoV-2 virus. A medical evaluation of these patients may be needed to prevent symptoms due to another disease being erroneously attributed to “long COVID.”
Bicuspid aortic valve (BAV), the most common cardiovascular malformation occurs in 0.5-1.2% of the population. Although highly heritable, few causal mutations have been identified in BAV patients. ...Here, we report the targeted sequencing of HOXA1 in a cohort of BAV patients and the identification of rare indel variants in the homopolymeric histidine tract of HOXA1. In vitro analysis shows that disruption of this motif leads to a significant reduction in protein half-life and defective transcriptional activity of HOXA1. In zebrafish, targeting hoxa1a ortholog results in aortic valve defects. In vivo assays indicates that these variants behave as dominant negatives leading abnormal valve development. In mice, deletion of Hoxa1 leads to BAV with a very small, rudimentary non-coronary leaflet. We also show that 17% of homozygous Hoxa1
knock-in mice present similar phenotype. Genetic lineage tracing in Hoxa1
mutant mice reveals an abnormal reduction of neural crest-derived cells in the valve leaflet, which is caused by a failure of early migration of these cells.
We performed whole-exome and whole-genome sequencing in 927 late-onset Alzheimer disease (LOAD) cases, 852 early-onset AD (EOAD) cases, and 1273 controls from France. We assessed the evidence for ...gene-based association of rare variants with AD in 6 genes for which an association with such variants was previously claimed. When aggregating protein-truncating and missense-predicted damaging variants, we found exome-wide significant association between EOAD risk and rare variants in SORL1, TREM2, and ABCA7. No exome-wide significant signal was obtained in the LOAD sample, and significance of the order of 10−6 was observed in the whole AD group for TREM2. Our study confirms previous gene-level results for TREM2, SORL1, and ABCA7 and provides a clearer insight into the classes of rare variants involved. Despite different effect sizes and varying cumulative minor allele frequencies, the rare protein-truncating and missense-predicted damaging variants in TREM2, SORL1, and ABCA7 contribute similarly to the heritability of EOAD and explain between 1.1% and 1.5% of EOAD heritability each, compared with 9.12% for APOE ε4.
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