Biology subjects

Eran, A.

Publications and source records attributed to Eran, A..

8 recordsLinked to original sources

bioRxiv2022

Detection of A-to-I microRNA editing with miRmedon reveals widespread co-editing of mature microRNA in the human brain

microRNA (miRNA), key regulators of gene expression, are prime targets for adenosine deaminase acting on RNA (ADAR) enzymes. Although ADAR-mediated adenosine-to-inosine (A-to-I) miRNA editing has been shown to be essential for orchestrating complex processes, including neurodevelopment and cancer progression, only few human miRNA editing sites have been reported. Several computational approaches have been developed for the detection of miRNA editing in small RNAseq data, all based on the identification of systematic mismatches of G at primary adenosine sites in known miRNA sequences. However, these methods have several limitations, including their ability to detect only one editing site per sequence (although editing of multiple sites per miRNA has been reproducibly validated), their focus on uniquely mapping reads (even though 20% of human miRNA are transcribed from multiple loci), and their inability to detect editing in miRNA harboring genomic variants (though 73% of human miRNA loci include a reported SNP or indel). To overcome these limitations, we developed miRmedon, that leverages large-scale human variation data, a combination of local and global alignments, and a comparison of the inferred editing and error distributions, for confident detection of miRNA editing in small RNAseq data. We demonstrate the improved performance of miRmedon as compared to currently available methods and describe its advantages. We further use miRmedon to discover editing haplotypes of mature human brain miRNA for the first time. We find that doubly edited mature miRNA are common in the adult human prefrontal cortex, most include a frequently edited site within the miRNA seed region, and are predicted to maintain a stable pre-miRNA structure. These results suggest that co-editing of mature miRNA could enable efficient shifting of gene expression programs.

bioinformatics↗

bioRxiv2022

IL-10 inhibits STAT1-dependent macrophage accumulation during microbiota-induced colitis

Loss of IL-10R function leads to severe early onset colitis and in murine models is associated with the accumulation of immature inflammatory colonic macrophages. We have shown that IL-10R-deficient colonic macrophages exhibit increased STAT1-dependent gene expression, suggesting that IL-10R-mediated inhibition of STAT1 signaling in newly recruited colonic macrophages might interfere with the development of an inflammatory phenotype. Indeed Stat1-/- mice exhibit defects in colonic macrophage accumulation following Helicobacter hepaticus infection and IL-10R blockade, and this was phenocopied in mice lacking IFNGR, an inducer of STAT1 activation. Radiation chimeras demonstrated that reduced accumulation of STAT1-deficient macrophages was based on a cell-intrinsic defect. Unexpectedly, mixed radiation chimeras generated with both WT and IL-10R-deficient bone marrow indicated that rather than directly interfering with STAT1 function, IL-10R prevents the generation of a cell extrinsic signal that promotes the accumulation of immature macrophages. These results define essential mechanisms controlling inflammatory macrophage accumulation in inflammatory bowel diseases. SummaryIntrinsic STAT1-function drives the accumulation of macrophages within the colon following the loss of IL-10R signaling. IL-10R prevents this STAT1-dependent process through a non-cell autonomous mechanism.

immunology↗

bioRxiv2022

Data-driven dissection of the Fever Effect in Autism Spectrum Disorder

Some individuals with autism spectrum disorder (ASD) demonstrate marked behavioral improvements during febrile episodes, in what is perhaps the only present-day means of modulating the core ASD phenotype. Understanding the nature of this so-called fever effect is therefore essential for leveraging this natural temporary relief of symptoms to a sustained efficacious intervention. Towards this goal, we used machine learning to analyze the rich clinical data of the Simons Simplex Collection, in which 1 out of every 6 children with ASD was reported to improve during febrile episodes, across multiple ASD domains. Reported behavioral improvements during febrile episodes were associated with maternal infection in pregnancy (OR = 1.7, 95% CI = [1.42, 2.03], P = 4.24x10-4) and gastrointestinal (GI) dysfunction (OR=1.46, 95% CI = [1.15, 1.81], P = 1.94x10-3). Family members of children reported to improve when febrile have an increased prevalence of autoimmune disorders (OR=1.43, 95% CI = [1.23, 1.67], P = 3.0x10-6), language disorders (OR=1.63, 95% CI = [1.29, 2.04], P = 2.5x10-5), and neuropsychiatric disorders (OR=1.59, 95% CI = [1.34, 1.89], P < 1x10-6). Since both GI abnormalities and maternal immune activation have been linked to ASD via proinflammatory cytokines, these results might suggest a possible involvement of immune dysregulation in the fever effect, consistent with findings in mouse models. This work advances our understanding of the fever-responsive ASD subtype and motivates future studies to directly test the link between proinflammatory cytokines and behavioral modifications in individuals with ASD. Lay summarySome individuals with ASD demonstrate marked behavioral improvements when they have a fever. However, the magnitude, scope, nature, and underlying neurobiological basis of the so-called fever effect remain unknown. This large-scale biomedical data analysis found that children with ASD reported to improve when febrile tend to be those with worse gastrointestinal symptoms and whose mothers reported an infection during pregnancy. These and other findings point to the involvement of proinflammatory cytokines in this phenomenon.

neuroscience↗

bioRxiv2022

The predictive value of double-stranded RNA for A-to-I editing detection

Structured AbstractO_ST_ABSMotivationC_ST_ABSAdenosine-to-inosine (A-to-I) RNA editing, a crucial reaction for many processes that contribute to transcriptome plasticity, is both widely common across the transcriptome and difficult to predict due to a lack of distinctive genomic characteristics that can be obtained and analyzed computationally. An exception to this is the secondary structure of RNA molecules, which has been shown to have a major impact on the selectivity and specificity of the enzymes responsible for A-to-I editing. Yet, this information is rarely used for the task of editing site prediction. ResultsHere, we demonstrated the value of using base-pairing probabilities of RNA nucleotides to classify genomic sites as A-to-I RNA editing sites, using large-scale truth data which we compiled and make available for use in training future models. Our analysis suggests that the span of four bases from -2 (upstream) to +1 (downstream) of a putative editing site is most informative in this regard. A classifier trained on base-pairing probabilities alone performed with a positive predictive value (PPV) of 0.68, a negative predictive value (NPV) of 0.64, and an area under the receiver operating characteristic curve (AUC) of 0.71. By identifying structure-related features that are informative for detecting A-to-I RNA editing sites and quantifying their predictive value, this work advances our understanding of A-to-I editing determinants. AvailabilityAll source codes and data are available at https://github.com/Ally-s-Lab/P-BEP

bioinformatics↗

bioRxiv2020

Melanocytes determine angiogenesis gene expression across human tissues

Several angiogenesis-dependent diseases, including age-related macular degeneration and infantile hemangioma, display differential prevalence among Black, as compared to White individuals. Although socioeconomic status and genetic architecture have been suggested as explaining these differences, we have recently shown that pigment production per se might be involved. For example, we have shown that the extracellular protein fibromodulin is a pro-angiogenic factor highly secreted by melanocytes in White but not Black individuals. Still, additional pigment-dependent angiogenic factors and their molecular mechanisms remain to be identified. Understanding the contribution of pigmentation to angiogenesis in health and disease is essential for precision medicine of angiogenesis-dependent diseases with racial disparity. Toward that goal, we compared the transcriptomes of Black and White individuals in three tissues with angiogenic activity, namely artery, whole blood, and skin. We identified several differentially expressed angiogenesis pathways, including artery morphogenesis, regulation of endothelial cell chemotaxis, and cellular response to vascular endothelial growth factor stimulus. We then demonstrated that the expression of key genes in these pathways is directly modulated by the degree of pigmentation. We further identified the precise pigment production pathway controlling the expression of these genes, namely melanocortin 1 receptor (MC1R) signaling. These results demonstrate pigment-mediated regulation of angiogenesis-related pathways and their driver genes across human tissues.

molecular biology↗

bioRxiv2019

miRmedon: confident detection of microRNA editing

microRNA (miRNA), key regulators of gene expression, are prime targets for adenosine deaminase acting on RNA (ADAR) enzymes. Although ADAR-mediated A-to-I miRNA editing has been shown to be essential for orchestrating complex processes, including neurodevelopment and cancer progression, only a few human miRNA editing sites have been reported. Several computational approaches have been developed for the detection of miRNA editing in small RNAseq data, all based on the identification of systematic mismatches of G at primary adenosine sites in known miRNA sequences. However, these methods have several limitations, including their ability to detect only one editing site per sequence (although editing of multiple sites per miRNA has been reproducibly validated), their focus on uniquely mapping reads (although 20% of human miRNA are transcribed from multiple loci), and their inability to detect editing in miRNA genes harboring genomic variants (although 73% of human miRNA loci include a reported SNP or indel). To overcome these limitations, we developed miRmedon, that leverages large scale human variation data, a combination of local and global alignments, and a comparison of the inferred editing and error distributions, for a confident detection of miRNA editing in small RNAseq data. We demonstrate its improved performance as compared to currently available methods and describe its advantages.\n\nAvailability and implementationPython source code is available at https://github.com/Amitai88/miRmedon\n\nContactalal@bgu.ac.il

bioinformatics↗

bioRxiv2019

Structural integrity following focused ultrasound thalamotomy and its correlation with tremor relief

BackgroundMagnetic-resonance-guided focused ultrasound ablation of ventral intermediate nucleus of the thalamus is a new treatment for tremor disorders.\n\nObjectivesWe sought to evaluate the white matter integrity prior to and following focused ultrasound ablation and its correlation with clinical outcome.\n\nMethods22 patients with essential tremor and 17 patients with Parkinsons disease underwent tremor and quality-of-life assessments prior to and at one and six months following focused ultrasound ablation. All patients underwent MRI including T1, T2-FLAIR and diffusion weighted imaging before treatment and at one day, 7-10 days, 1-3 months, and 6 months or more following it. Diffusivity parameters were calculated and fiber tractography measures were extracted. Change in diffusivity parameters were assessed inside the ablated core, in the motor thalamus and throughout the dentato-rubro-thalamo-cortical tract.\n\nResultsWe found short-term changes in the motor thalamus and in the tract between the thalamus and regions within the dentato-rubro-thalamo-cortical tract. Long term damage was found in the ablated core and in the tract connecting the thalamus and red-nucleus. Inverse correlation was found between fractional anisotropy in the motor thalamus one day following ablation and tremor improvement in both patient groups, with lower values before treatment associated with better outcome (tremor relief) in essential tremor patients.\n\nConclusionsShort-and long-term changes in white matter integrity are present following focused ultrasound thalamotomy. Regions demonstrating long-term white matter changes may be responsible for the tremor relief seen in patients, implicating these regions in the disorders pathogenesis.

neuroscience↗

bioRxiv2018

mtDNA eQTLs and the m1A 16S rRNA modification explain mtDNA tissue-specific gene expression pattern in humans

Expression quantitative trait loci (eQTLs) are instrumental in genome-wide identification of regulatory elements, yet were overlooked in the mitochondrial DNA (mtDNA). By analyzing 5079 RNA-seq samples from 23 tissues we identified association of ancient mtDNA SNPs (haplogroups T2, L2, J2 and V) and recurrent SNPs (mtDNA positions 263, 750, 1438 and 10398) with tissue-dependent mtDNA gene-expression. Since the recurrent SNPs independently occurred in different mtDNA genetic backgrounds, they constitute the best candidates to be causal eQTLs. Secondly, the discovery of mtDNA eQTLs in both coding and non-coding mtDNA regions, propose the identification of novel mtDNA regulatory elements. Third, we identified association between low m1A 947 MT-RNR2 (16S) rRNA modification levels and altered mtDNA gene-expression in twelve tissues. Such association disappeared in skin which was exposed to sun, as compared to sun-unexposed skin from the same individuals, thus supporting the impact of UV on mtDNA gene expression. Taken together, our findings reveal that both mtDNA SNPs and mt-rRNA modification affect mtDNA gene expression in a tissue-dependent manner.

genomics↗